143 results on '"David Masopust"'
Search Results
2. Tissue-resident memory T cells trigger rapid exudation and local antibody accumulation
- Author
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Pamela C. Rosato, Sahar Lotfi-Emran, Vineet Joag, Sathi Wijeyesinghe, Clare F. Quarnstrom, Hanna N. Degefu, Rebecca Nedellec, Jason M. Schenkel, Lalit K. Beura, Lars Hangartner, Dennis R. Burton, and David Masopust
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Immunology ,Immunology and Allergy - Published
- 2023
3. Functional T cells are capable of supernumerary cell division and longevity
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Andrew G. Soerens, Marco Künzli, Clare F. Quarnstrom, Milcah C. Scott, Lee Swanson, JJ. Locquiao, Hazem E. Ghoneim, Dietmar Zehn, Benjamin Youngblood, Vaiva Vezys, and David Masopust
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Multidisciplinary - Published
- 2023
4. Novel Lymphocytic Choriomeningitis Virus Strain Sustains Abundant Exhausted Progenitor CD8 T Cells without Systemic Viremia
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Lalit K. Beura, Milcah C. Scott, Mark J. Pierson, Vineet Joag, Sathi Wijeyesinghe, Matthew R. Semler, Clare F. Quarnstrom, Kathleen Busman-Sahay, Jacob D. Estes, Sara E. Hamilton, Vaiva Vezys, David H. O’Connor, and David Masopust
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Mice, Inbred C57BL ,Mice ,Programmed Cell Death 1 Receptor ,Immunology ,Animals ,Lymphocytic choriomeningitis virus ,Immunology and Allergy ,Viremia ,Amino Acids ,CD8-Positive T-Lymphocytes ,Lymphocytic Choriomeningitis ,Hepatitis A Virus Cellular Receptor 2 - Abstract
Lymphocytic choriomeningitis virus (LCMV) is the prototypic arenavirus and a natural mouse pathogen. LCMV-Armstrong, an acutely resolved strain, and LCMV-clone 13, a mutant that establishes chronic infection, have provided contrasting infection models that continue to inform the fundamental biology of T cell differentiation, regulation of exhaustion, and response to checkpoint blockade. In this study, we report the isolation and characterization of LCMV-Minnesota (LCMV-MN), which was naturally transmitted to laboratory mice upon cohousing with pet shop mice and shares 80–95% amino acid homology with previously characterized LCMV strains. Infection of laboratory mice with purified LCMV-MN resulted in viral persistence that was intermediate between LCMV-Armstrong and -clone 13, with widely disseminated viral replication and viremia that was controlled within 15–30 d, unless CD4 T cells were depleted prior to infection. LCMV-MN–responding CD8+ T cells biased differentiation toward the recently described programmed death-1 (PD-1)+CXCR5+Tim-3lo stemlike CD8+ T cell population (also referred to as progenitor exhausted T cells) that effectuates responses to PD-1 blockade checkpoint inhibition, a therapy that rejuvenates responses against chronic infections and cancer. This subset resembled previously characterized PD-1+TCF1+ stemlike CD8+ T cells by transcriptional, phenotypic, and functional assays, yet was atypically abundant. LCMV-MN may provide a tool to better understand the breadth of immune responses in different settings of chronic Ag stimulation as well as the ontogeny of progenitor exhausted T cells and the regulation of responsiveness to PD-1 blockade.
- Published
- 2022
5. Depleting CD103+ resident memory T cells in vivo reveals immunostimulatory functions in oral mucosa
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J. Michael Stolley, Milcah C. Scott, Vineet Joag, Alexander J. Dale, Timothy S. Johnston, Flavia Saavedra, Noah V. Gavil, Sahar Lotfi-Emran, Andrew G. Soerens, Eyob Weyu, Mark J. Pierson, Mark C. Herzberg, Nu Zhang, Vaiva Vezys, and David Masopust
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Immunology ,Immunology and Allergy - Abstract
The oral mucosa is a frontline for microbial exposure and juxtaposes several unique tissues and mechanical structures. Based on parabiotic surgery of mice receiving systemic viral infections or co-housing with microbially diverse pet shop mice, we report that the oral mucosa harbors CD8+ CD103+ resident memory T cells (TRM), which locally survey tissues without recirculating. Oral antigen re-encounter during the effector phase of immune responses potentiated TRM establishment within tongue, gums, palate, and cheek. Upon reactivation, oral TRM triggered changes in somatosensory and innate immune gene expression. We developed in vivo methods for depleting CD103+ TRM while sparing CD103neg TRM and recirculating cells. This revealed that CD103+ TRM were responsible for inducing local gene expression changes. Oral TRM putatively protected against local viral infection. This study provides methods for generating, assessing, and in vivo depleting oral TRM, documents their distribution throughout the oral mucosa, and provides evidence that TRM confer protection and trigger responses in oral physiology and innate immunity.
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- 2023
6. Responsiveness to interleukin-15 therapy is shared between tissue-resident and circulating memory CD8
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Nicholas N, Jarjour, Kelsey M, Wanhainen, Changwei, Peng, Noah V, Gavil, Nicholas J, Maurice, Henrique, Borges da Silva, Ryan J, Martinez, Talia S, Dalzell, Matthew A, Huggins, David, Masopust, Sara E, Hamilton, and Stephen C, Jameson
- Subjects
Interleukin-15 ,T-Lymphocyte Subsets ,CD8-Positive T-Lymphocytes ,Immunologic Memory - Abstract
Interleukin-15 (IL-15) is often considered a central regulator of memory CD8
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- 2023
7. FGL2-targeting T cells exhibit antitumor effects on glioblastoma and recruit tumor-specific brain-resident memory T cells
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Qingnan Zhao, Jiemiao Hu, Lingyuan Kong, Shan Jiang, Xiangjun Tian, Jing Wang, Rintaro Hashizume, Zhiliang Jia, Natalie Wall Fowlkes, Jun Yan, Xueqing Xia, Sofia F. Yi, Long Hoang Dao, David Masopust, Amy B. Heimberger, and Shulin Li
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Multidisciplinary ,General Physics and Astronomy ,General Chemistry ,General Biochemistry, Genetics and Molecular Biology - Abstract
Although tissue-resident memory T (TRM) cells specific for previously encountered pathogens have been characterized, the induction and recruitment of brain TRM cells following immune therapy has not been observed in the context of glioblastoma. Here, we show that T cells expressing fibrinogen-like 2 (FGL2)–specific single-chain variable fragments (T-αFGL2) can induce tumor-specific CD8+ TRM cells that prevent glioblastoma recurrence. These CD8+ TRM cells display a highly expanded T cell receptor repertoire distinct from that found in peripheral tissue. When adoptively transferred to the brains of either immunocompetent or T cell-deficient naïve mice, these CD8+ TRM cells reject glioma cells. Mechanistically, T-αFGL2 cell treatment increased the number of CD69+CD8+ brain-resident memory T cells in tumor-bearing mice via a CXCL9/10 and CXCR3 chemokine axis. These findings suggest that tumor-specific brain-resident CD8+ TRM cells may have promising implications for the prevention of brain tumor recurrence.
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- 2023
8. 1027 Chronic antigen in solid tumors drives a distinct program of T cell residence
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Noah Gavil, Milcah Scott, Eyob Weyu, Olivia Smith, Stephen O'Flanagan, Sathi Wijeyesinghe, Sahar Lotfi-Emran, Stephen Shiao, Vaiva Vezys, and David Masopust
- Published
- 2022
9. Responsiveness to interleukin-15 therapy is shared between tissue-resident and circulating memory CD8 + T cell subsets
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Nicholas N. Jarjour, Kelsey M. Wanhainen, Changwei Peng, Noah V. Gavil, Nicholas J. Maurice, Henrique Borges da Silva, Ryan J. Martinez, Talia S. Dalzell, Matthew A. Huggins, David Masopust, Sara E. Hamilton, and Stephen C. Jameson
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Multidisciplinary - Abstract
Interleukin-15 (IL-15) is often considered a central regulator of memory CD8 + T cells, based primarily on studies of recirculating subsets. However, recent work identified IL-15–independent CD8 + T cell memory populations, including tissue-resident memory CD8 + T cells (T RM ) in some nonlymphoid tissues (NLTs). Whether this reflects the existence of IL-15–insensitive memory CD8 + T cells is unclear. We report that IL-15 complexes (IL-15c) stimulate rapid proliferation and expansion of both tissue-resident and circulating memory CD8 + T cell subsets across lymphoid and nonlymphoid tissues with varying magnitude by tissue and memory subset, in some sites correlating with differing levels of the IL-2Rβ. This was conserved for memory CD8 + T cells recognizing distinct antigens and elicited by different pathogens. Following IL-15c–induced expansion, divided cells contracted to baseline numbers and only slowly returned to basal proliferation, suggesting a mechanism to transiently amplify memory populations. Through parabiosis, we showed that IL-15c drive local proliferation of T RM , with a degree of recruitment of circulating cells to some NLTs. Hence, irrespective of homeostatic IL-15 dependence, IL-15 sensitivity is a defining feature of memory CD8 + T cell populations, with therapeutic potential for expansion of T RM and other memory subsets in an antigen-agnostic and temporally controlled fashion.
- Published
- 2022
10. Correction to: Functional virus‑specific memory T cells survey glioblastoma
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Jianfang Ning, Noah V. Gavil, Shaoping Wu, Sathi Wijeyesinghe, Eyob Weyu, Jun Ma, Ming Li, Florina‑Nicoleta Grigore, Sanjay Dhawan, Alexander G. J. Skorput, Shawn C. Musial, Clark C. Chen, David Masopust, and Pamela C. Rosato
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Cancer Research ,Oncology ,Immunology ,Immunology and Allergy - Published
- 2022
11. Differential migration mechanics and immune responses of glioblastoma subtypes
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Ghaidan A. Shamsan, Chao J. Liu, Brooke C. Braman, Susan K. Rathe, Aaron L. Sarver, Nima Ghaderi, Mariah M. McMahon, Rebecca L. Klank, Barbara R. Tschida, S. Joey McFarren, Pamela C. Rosato, David Masopust, Jann N. Sarkaria, H. Brent Clark, Steven S. Rosenfeld, David A. Largaespada, and David J. Odde
- Abstract
SUMMARYGlioblastoma remains a deadly cancer driven by invasion of tumor cells into the brain. Transcriptomic analyses have revealed distinct molecular subtypes, but mechanistic differences that explain clinical differences are not clear. Here, we show that, as predicted by the motor-clutch model for cell migration, mesenchymal glioma cells are more spread, generate larger traction forces, and migrate faster in brain tissue compared to proneural cells. Despite their fast migration and comparable proliferation rate in vitro, mice with mesenchymal tumors live longer than mice with proneural tumors, which was correlated with an immune response in the mesenchymal mice that included T cell-mediated killing of cancer cells, similar to human tumors. Thus, mesenchymal tumors have aggressive migration, but are relatively immunologically ‘hot’ which suppresses net proliferation. These two features counteract each other and may explain the lack of a strong survival difference between subtypes clinically, while also opening up new opportunities for subtype-specific therapies.
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- 2022
12. Route of self-amplifying mRNA vaccination modulates the establishment of pulmonary resident memory CD8 and CD4 T cells
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Marco Künzli, Stephen D. O’Flanagan, Madeleine LaRue, Poulami Talukder, Thamotharampillai Dileepan, Andrew G. Soerens, Clare F. Quarnstrom, Sathi Wijeyesinghe, Yanqi Ye, Justine McPartlan, Jason S. Mitchell, Christian W. Mandl, Richard Vile, Marc K. Jenkins, Rafi Ahmed, Vaiva Vezys, Jasdave Chahal, and David Masopust
- Abstract
Respiratory tract resident memory T cells (Trm), typically generated by local vaccination or infection, can accelerate control of pulmonary infections that evade neutralizing antibody. It is unknown whether mRNA vaccination establishes respiratory Trm. We generated a self-amplifying mRNA vaccine encoding the influenza A virus nucleoprotein that is encapsulated in modified dendron-based nanoparticles. Here we report how routes of immunization in mice, including contralateral versus ipsilateral intramuscular boosts, or intravenous and intranasal routes, influence influenza-specific cell-mediated and humoral immunity. Parabiotic surgeries revealed that intramuscular immunization was sufficient to establish CD8 Trm in lung and draining lymph node. Contralateral, compared to ipsilateral, intramuscular boosting broadened the distribution of LN Trm and T follicular helper cells, but slightly diminished resulting levels of serum antibody. Intranasal mRNA delivery established modest circulating CD8 and CD4 T cell memory, but augmented distribution to the respiratory mucosa. Of note, combining intramuscular immunizations with an intranasal mRNA boost achieved high levels of both circulating T cell memory and lung Trm. Thus, routes of mRNA vaccination influence humoral and cell-mediated immunity, and intramuscular prime-boosting establishes lung Trm that can be further enhanced by an additional intranasal immunization.
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- 2022
13. FGL2-targeted T cells induced tumor-specific brain resident TRM cells preventing glioblastoma recurrence
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Qingnan Zhao, Ling-Yuan Kong, Shan Jiang, Xiangjun Tian, Jing Wang, Rintaro Hashizume, Jiemiao Hu, Zhiliang Jia, Natalie Fowlkes, Jun Yan, Xeuqing Xia, Sofia Yi, Long Dao, David Masopust, Hideho Okada, Amy Heimberger, and Shulin Li
- Abstract
Tissue-resident memory T cells (TRM) specific to previously encountered pathogens have been characterized, but tumor-specific TRM cells in brain have not been reported in the literature. We discovered that T cells armed with FGL2-blocking single-chain variable fragments (T-αFGL2) are able to induce tumor-specific CD8+TRM cells, which prevent glioblastoma recurrence, a major obstacle in achieving long term survivors. These tumor-specific CD8+TRM displayed a unique highly expanded T cell receptor repertoire distinct from that found in peripheral tissues. Notably, these CD8+TRM cells could be transplanted into the brains of either immunocompetent or T cell deficient naïve mice, transforming them to become immune reactive to tumor cells. The mechanism study found T-αFGL2 therapy boosted CD69+CD8+ memory T cells population in tumor bearing brains, which depend on CXCL9/10-CXCR3 signaling. These findings are the first to show tumor-specific brain resident CD8+TRM generation via adoptive cellular treatment and may have promising implications for cancer immunotherapy.
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- 2022
14. Natural rodent model of viral transmission reveals biological features of virus population dynamics
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Elizabeth J. Fay, Keir M. Balla, Shanley N. Roach, Frances K. Shepherd, Dira S. Putri, Talia D. Wiggen, Stephen A. Goldstein, Mark J. Pierson, Martin T. Ferris, Claire E. Thefaine, Andrew Tucker, Mark Salnikov, Valerie Cortez, Susan R. Compton, Sergei V. Kotenko, Ryan C. Hunter, David Masopust, Nels C. Elde, and Ryan A. Langlois
- Subjects
viruses ,Knockout ,Immunology ,Rodentia ,Medical and Health Sciences ,Animal Diseases ,Vaccine Related ,Mice ,Biodefense ,Immunology and Allergy ,Animals ,Humans ,2.1 Biological and endogenous factors ,2.2 Factors relating to the physical environment ,Aetiology ,Mice, Knockout ,Animal ,Prevention ,Disease Models, Animal ,Emerging Infectious Diseases ,Infectious Diseases ,Virus Diseases ,Disease Models ,Host-Pathogen Interactions ,Microbial Interactions ,Disease Susceptibility ,Interferons ,Infection ,Biomarkers - Abstract
Emerging viruses threaten global health, but few experimental models can characterize the virus and host factors necessary for within- and cross-species transmission. Here, we leverage a model whereby pet store mice or rats—which harbor natural rodent pathogens—are cohoused with laboratory mice. This “dirty” mouse model offers a platform for studying acute transmission of viruses between and within hosts via natural mechanisms. We identified numerous viruses and other microbial species that transmit to cohoused mice, including prospective new members of the Coronaviridae, Astroviridae, Picornaviridae, and Narnaviridae families, and uncovered pathogen interactions that promote or prevent virus transmission. We also evaluated transmission dynamics of murine astroviruses during transmission and spread within a new host. Finally, by cohousing our laboratory mice with the bedding of pet store rats, we identified cross-species transmission of a rat astrovirus. Overall, this model system allows for the analysis of transmission of natural rodent viruses and is a platform to further characterize barriers to zoonosis.
- Published
- 2022
15. T cell-inducing vaccine durably prevents mucosal SHIV infection even with lower neutralizing antibody titers
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Traci Legere, Pradeep B. J. Reddy, Korey A. Walter, Bali Pulendran, Prabhu S. Arunachalam, Shankar Subramaniam, Florian Wimmers, Madeleine K D Scott, Celia C. LaBranche, Bertrand Z. Yeung, John P. Vasilakos, Venkata S. Bollimpelli, Samantha L. Burton, Sailaja Gangadhara, Sudhir Pai Kasturi, Shakti Gupta, Cynthia A. Derdeyn, Caroline Petitdemange, Pamela A. Kozlowski, David C. Montefiori, Tiffany M. Styles, Thomas J. Ketas, John P. Moore, Chil Yong Kang, Rama Rao Amara, Eric Hunter, George M. Shaw, Purvesh Khatri, Mark A. Tomai, Anthony Tsai, David Masopust, Vineet Joag, Clare F. Quarnstrom, and Tysheena P. Charles
- Subjects
CD4-Positive T-Lymphocytes ,Cellular immunity ,T cell ,Genetic Vectors ,Immunology ,Simian Acquired Immunodeficiency Syndrome ,Gene Products, gag ,Diseases ,CD8-Positive T-Lymphocytes ,Antibodies, Viral ,Immunity, Heterologous ,Article ,General Biochemistry, Genetics and Molecular Biology ,Viral vector ,Immunogenicity, Vaccine ,Immune system ,Immunity ,medicine ,Animals ,HIV vaccine ,Neutralizing antibody ,Immunity, Cellular ,Mucous Membrane ,biology ,business.industry ,SAIDS Vaccines ,General Medicine ,Antibodies, Neutralizing ,Macaca mulatta ,Virology ,medicine.anatomical_structure ,Vagina ,biology.protein ,Female ,Simian Immunodeficiency Virus ,Antibody ,business ,Immunologic Memory - Abstract
Recent efforts toward an HIV vaccine focus on inducing broadly neutralizing antibodies, but eliciting both neutralizing antibodies (nAbs) and cellular responses may be superior. Here, we immunized macaques with an HIV envelope trimer, either alone to induce nAbs, or together with a heterologous viral vector regimen to elicit nAbs and cellular immunity, including CD8+ tissue-resident memory T cells. After ten vaginal challenges with autologous virus, protection was observed in both vaccine groups at 53.3% and 66.7%, respectively. A nAb titer >300 was generally associated with protection but in the heterologous viral vector + nAb group, titers, An HIV vaccine that elicits both antibodies and cellular immune responses confers long-lasting protection against viral challenge in nonhuman primates.
- Published
- 2020
16. PD-1+ stemlike CD8 T cells are resident in lymphoid tissues during persistent LCMV infection
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Se Jin Im, Bogumila T. Konieczny, William H. Hudson, Rafi Ahmed, and David Masopust
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Receptors, CXCR5 ,0301 basic medicine ,Lymphoid Tissue ,Parabiosis ,viruses ,Programmed Cell Death 1 Receptor ,Population ,CD8-Positive T-Lymphocytes ,Lymphocytic Choriomeningitis ,Biology ,Lymphocytic choriomeningitis ,Virus ,CXCR5 ,Mice ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,Humans ,Lymphocytic choriomeningitis virus ,Cytotoxic T cell ,education ,Hepatitis A Virus Cellular Receptor 2 ,education.field_of_study ,Multidisciplinary ,Biological Sciences ,medicine.disease ,Mice, Inbred C57BL ,Chronic infection ,030104 developmental biology ,Immunology ,T cell migration ,Female ,Immunologic Memory ,030215 immunology - Abstract
The migratory patterns of virus-specific CD8 T cells during chronic viral infection are not well understood. To address this issue, we have done parabiosis experiments during chronic lymphocytic choriomeningitis virus (LCMV) infection of mice. We found that despite the high frequency of virus-specific CD8 T cells in both lymphoid and nonlymphoid tissues there was minimal migration of virus-specific CD8 T cells between the chronically infected conjoined parabiont mice. This was in contrast to parabionts between mice that had undergone an acute LCMV infection where virus-specific CD8 T cells established equilibrium demonstrating circulation of memory T cells generated after viral clearance. We have identified a population of PD-1+ TCF1+CXCR5+Tim-3- stemlike virus-specific CD8 T cells that reside in lymphoid tissues and act as resource cells for maintaining the T cell response during chronic infection. These are the cells that proliferate and give rise to the more terminally differentiated PD-1+ CXCR5-Tim-3+ CD8 T cells. Both the stemlike CD8 T cells and their terminally differentiated progeny showed minimal migration during chronic infection and the few LCMV-specific CD8 T cells that were present in circulation were the recently emerging progeny from the stemlike CD8 T cells. The PD-1+ TCF1+CXCR5+ stemlike CD8 T cells were truly resident in lymphoid tissues and did not circulate in the blood. We propose that this residency in specialized niches within lymphoid tissues is a key aspect of their biology and is essential for maintaining their quiescence and stemlike program under conditions of a chronic viral infection.
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- 2020
17. Lung-resident memory B cells established after pulmonary influenza infection display distinct transcriptional and phenotypic profiles
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Hyon-Xhi, Tan, Jennifer A, Juno, Robyn, Esterbauer, Hannah G, Kelly, Kathleen M, Wragg, Penny, Konstandopoulos, Sheilajen, Alcantara, Carolina, Alvarado, Robert, Jones, Graham, Starkey, Boa Zhong, Wang, Osamu, Yoshino, Thomas, Tiang, M Lindsay, Grayson, Helen, Opdam, Rohit, D'Costa, Angela, Vago, Laura K, Mackay, Claire L, Gordon, David, Masopust, Joanna R, Groom, Stephen J, Kent, and Adam K, Wheatley
- Subjects
Mice, Knockout ,Immunology ,Mice, Transgenic ,General Medicine ,Mice, Inbred C57BL ,Mice ,Phenotype ,Memory B Cells ,Orthomyxoviridae Infections ,Influenza, Human ,Animals ,Humans ,Female ,Lung - Abstract
Recent studies have established that memory B cells, largely thought to be circulatory in the blood, can take up long-term residency in inflamed tissues, analogous to widely described tissue-resident T cells. The dynamics of recruitment and retention of memory B cells to tissues and their immunological purpose remains unclear. Here, we characterized tissue-resident memory B cells (B RM ) that are stably maintained in the lungs of mice after pulmonary influenza infection. Influenza - specific B RM were localized within inducible bronchus-associated lymphoid tissues (iBALTs) and displayed transcriptional signatures distinct from classical memory B cells in the blood or spleen while showing partial overlap with memory B cells in lung-draining lymph nodes. We identified lung-resident markers, including elevated expression of CXCR3, CCR6, and CD69, on hemagglutinin (HA)– and nucleoprotein (NP)–specific lung B RM . We found that CCR6 facilitates increased recruitment and/or retention of B RM in lungs and differentiation into antibody-secreting cells upon recall. Although expression of CXCR3 and CCR6 was comparable in total and influenza-specific memory B cells isolated across tissues of human donors, CD69 expression was higher in memory B cells from lung and draining lymph nodes of human organ donors relative to splenic and PBMC-derived populations, indicating that mechanisms underpinning B RM localization may be evolutionarily conserved. Last, we demonstrate that human memory B cells in lungs are transcriptionally distinct to populations in lung-draining lymph nodes or PBMCs. These data suggest that B RM may constitute a discrete component of B cell immunity, positioned at the lung mucosa for rapid humoral response against respiratory viral infections.
- Published
- 2022
18. Functional virus-specific memory T cells survey glioblastoma
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Jianfang Ning, Noah V. Gavil, Shaoping Wu, Sathi Wijeyesinghe, Eyob Weyu, Jun Ma, Ming Li, Florina-Nicoleta Grigore, Sanjay Dhawan, Alexander G. J. Skorput, Shawn C. Musial, Clark C. Chen, David Masopust, and Pamela C. Rosato
- Subjects
Cancer Research ,Brain Neoplasms ,Immunology ,Article ,Memory T Cells ,Mice ,Oncology ,Immune Tolerance ,Tumor Microenvironment ,Immunology and Allergy ,Animals ,Humans ,Immunotherapy ,Glioblastoma - Abstract
Glioblastoma multiforme (GBM) is among the most aggressive, treatment-resistant cancers, and despite standard of care surgery, radiation and chemotherapy, is invariably fatal. GBM is marked by local and systemic immunosuppression, contributing to resistance to existing immunotherapies that have had success in other tumor types. Memory T cells specific for previous infections reside in tissues throughout the host and are capable of rapid and potent immune activation. Here, we show that virus-specific memory CD8 + T cells expressing tissue-resident markers populate the mouse and human glioblastoma microenvironment. Reactivating virus-specific memory T cells through intratumoral delivery of adjuvant-free virus-derived peptide triggered local immune activation. This delivery translated to antineoplastic effects, which improved survival in a murine glioblastoma model. Our results indicate that virus-specific memory T cells are a significant part of the glioblastoma immune microenvironment and may be leveraged to promote anti-tumoral immunity.
- Published
- 2021
19. Therapeutic activation of virus-specific resident memory T cells within the glioblastoma microenvironment
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Noah V. Gavil, Jianfang Ning, Shawn C. Musial, Sanjay Dhawan, David Masopust, Shaoping Wu, Pamela C. Rosato, Eyob Weyu, Jun Ma, Florina-Nicoleta Grigore, Alexander G. J. Skorput, Clark C. Chen, Sathi Wijeyesinghe, and Ming Li
- Subjects
Chemotherapy ,Systemic immunosuppression ,business.industry ,medicine.medical_treatment ,Improved survival ,medicine.disease ,Virus ,Immunity ,Cancer research ,medicine ,business ,CD8 ,Immune activation ,Glioblastoma - Abstract
Glioblastoma multiforme (GBM) is among the most aggressive, treatment resistant cancers, and despite standard of care surgery, radiation and chemotherapy, is invariably fatal. GBM is marked by local and systemic immunosuppression, contributing to resistance to existing immunotherapies that have had success in other tumor types. Memory T cells specific for previous infections reside in tissues throughout the host and these tissue resident memory T cells (TRM) are capable of rapid and potent immune activation. Here, we show that virus-specific memory CD8+ T cells expressing tissue resident markers populate mouse and human glioblastoma microenvironment. Reactivating virus-specific TRM through intra-tumoral delivery of adjuvant-free virus-derived peptide triggered local immune activation. This delivery translated to anti-neoplastic effects, which improved survival in a murine glioblastoma model. Our results indicate that virus-specific TRM are a significant part of the glioblastoma immune microenvironment and can be leveraged to promote anti-tumoral immunity.
- Published
- 2021
20. Cutting Edge: Nucleocapsid Vaccine Elicits Spike-Independent SARS-CoV-2 Protective Immunity
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Vineet Joag, Stephen D O'Flanagan, Joshua M. Thiede, Clare F. Quarnstrom, Clayton K. Mickelson, Marc K. Jenkins, J. Michael Stolley, William E. Matchett, Tyler D. Bold, David Masopust, Michelle N Vu, Vaiva Vezys, Frances K. Shepherd, Vineet D. Menachery, Jennifer A Walter, Samuel Becker, Sathi Wijeyesinghe, Ryan A. Langlois, Eyob Weyu, and Andrew G. Soerens
- Subjects
Male ,COVID-19 Vaccines ,viruses ,T cell ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Immunology ,Biology ,CD8-Positive T-Lymphocytes ,Antibodies, Viral ,Epitope ,Article ,Cell Line ,Mice ,Immunity ,Cricetinae ,Pandemic ,Chlorocebus aethiops ,medicine ,Immunology and Allergy ,Animals ,Coronavirus Nucleocapsid Proteins ,Vector (molecular biology) ,Lymphocyte Count ,Vero Cells ,SARS-CoV-2 ,Vaccination ,COVID-19 ,Phosphoproteins ,Virology ,Antibodies, Neutralizing ,Mice, Inbred C57BL ,medicine.anatomical_structure ,biology.protein ,Female ,Antibody ,Viral load ,Immunologic Memory - Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the COVID-19 pandemic. Neutralizing Abs target the receptor binding domain of the spike (S) protein, a focus of successful vaccine efforts. Concerns have arisen that S-specific vaccine immunity may fail to neutralize emerging variants. We show that vaccination with a human adenovirus type 5 vector expressing the SARS-CoV-2 nucleocapsid (N) protein can establish protective immunity, defined by reduced weight loss and viral load, in both Syrian hamsters and K18-hACE2 mice. Challenge of vaccinated mice was associated with rapid N-specific T cell recall responses in the respiratory mucosa. This study supports the rationale for including additional viral Ags in SARS-CoV-2 vaccines, even if they are not a target of neutralizing Abs, to broaden epitope coverage and immune effector mechanisms.
- Published
- 2021
21. The Impact of TCR Signal Strength on Resident Memory T Cell Formation during Influenza Virus Infection
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Sathi Wijeyesinghe, Matthew W. Markman, David Masopust, Marissa Macchietto, Ian A. Stone, Ryan A. Langlois, Steven S. Shen, Jessica K. Fiege, and Elizabeth J. Fay
- Subjects
Immunology ,Receptors, Antigen, T-Cell ,Heterologous ,Stimulation ,Biology ,medicine.disease_cause ,Article ,Virus ,Epitope ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Orthomyxoviridae Infections ,T-Lymphocyte Subsets ,medicine ,Influenza A virus ,Animals ,Immunology and Allergy ,T-cell receptor ,Cell Differentiation ,Phenotype ,Cell biology ,Mice, Inbred C57BL ,medicine.anatomical_structure ,Female ,Immunologic Memory ,Memory T cell ,Signal Transduction ,030215 immunology - Abstract
Resident memory T cells (TRM) in the lung are vital for heterologous protection against influenza A virus (IAV). Environmental factors are necessary to establish lung TRM; however, the role of T cell–intrinsic factors like TCR signal strength have not been elucidated. In this study, we investigated the impact of TCR signal strength on the generation and maintenance of lung TRM after IAV infection. We inserted high- and low-affinity OT-I epitopes into IAV and infected mice after transfer of OT-I T cells. We uncovered a bias in TRM formation in the lung elicited by lower affinity TCR stimulation. TCR affinity did not impact the overall phenotype or long-term maintenance of lung TRM. Overall, these findings demonstrate that TRM formation is negatively correlated with increased TCR signal strength. Lower affinity cells may have an advantage in forming TRM to ensure diversity in the Ag-specific repertoire in tissues.
- Published
- 2019
22. The Functional Requirement for CD69 in Establishment of Resident Memory CD8+ T Cells Varies with Tissue Location
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Sara E. Hamilton, Lalit K. Beura, David Masopust, Daniel Walsh, Changwei Peng, Henrique Borges da Silva, and Stephen C. Jameson
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Antigens, Differentiation, T-Lymphocyte ,Immunology ,Mutant ,chemical and pharmacologic phenomena ,CD8-Positive T-Lymphocytes ,Biology ,Article ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Antigens, CD ,T-Lymphocyte Subsets ,medicine ,Animals ,Immunology and Allergy ,Cytotoxic T cell ,Lectins, C-Type ,S1PR1 ,Kidney ,CD69 ,hemic and immune systems ,Small intestine ,Cell biology ,medicine.anatomical_structure ,KLF2 ,Immunologic Memory ,CD8 ,030215 immunology - Abstract
Recent studies have characterized populations of memory CD8+ T cells that do not recirculate through the blood but are, instead, retained in nonlymphoid tissues. Such CD8+ tissue resident memory T cells (TRM) are critical for pathogen control at barrier sites. Identifying TRM and defining the basis for their tissue residency is therefore of considerable importance for understanding protective immunity and improved vaccine design. Expression of the molecule CD69 is widely used as a definitive marker for TRM, yet it is unclear whether CD69 is universally required for producing or retaining TRM. Using multiple mouse models of acute immunization, we found that the functional requirement for CD69 was highly variable, depending on the tissue examined, playing no detectable role in generation of TRM at some sites (such as the small intestine), whereas CD69 was critical for establishing resident cells in the kidney. Likewise, forced expression of CD69 (but not expression of a CD69 mutant unable to bind the egress factor S1PR1) promoted CD8+ TRM generation in the kidney but not in other tissues. Our findings indicate that the functional relevance of CD69 in generation and maintenance of CD8+ TRM varies considerably, chiefly dependent on the specific nonlymphoid tissue studied. Together with previous reports that suggest uncoupling of CD69 expression and tissue residency, these findings prompt caution in reliance on CD69 expression as a consistent marker of CD8+ TRM.
- Published
- 2019
23. Tissue-Resident T Cells and Other Resident Leukocytes
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David Masopust and Andrew G. Soerens
- Subjects
CD4-Positive T-Lymphocytes ,medicine.medical_specialty ,Immunology ,CD8-Positive T-Lymphocytes ,Biology ,Article ,Immune system ,Medical microbiology ,Cell Movement ,Immunity ,Leukocytes ,medicine ,Animals ,Humans ,Immunology and Allergy ,book ,B-Lymphocytes ,Macrophages ,Venous blood ,Immunity, Innate ,Killer Cells, Natural ,medicine.anatomical_structure ,Organ Specificity ,Pediatric Infectious Disease ,book.journal ,Immunologic Memory ,Memory T cell - Abstract
Resident memory T (Trm) cells stably occupy tissues and cannot be sampled in superficial venous blood. Trm cells are heterogeneous but collectively constitute the most abundant memory T cell subset. Trm cells form an integral part of the immune sensing network, monitor for local perturbations in homeostasis throughout the body, participate in protection from infection and cancer, and likely promote autoimmunity, allergy, and inflammatory diseases and impede successful transplantation. Thus Trm cells are major candidates for therapeutic manipulation. Here we review CD8+ and CD4+ Trm ontogeny, maintenance, function, and distribution within lymphoid and nonlymphoid tissues and strategies for their study. We briefly discuss other resident leukocyte populations, including innate lymphoid cells, macrophages, natural killer and natural killer T cells, nonclassical T cells, and memory B cells. Lastly, we highlight major gaps in knowledge and propose ways in which a deeper understanding could result in new methods to prevent or treat diverse human diseases.
- Published
- 2019
24. Leveraging Resident Memory T Cells to Fortify Oral Immunity
- Author
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Michael Stolley and David Masopust
- Subjects
Immunology ,Immunology and Allergy - Abstract
Resident memory T cells (TRM) durably survey barrier tissues for reinfection and orchestrate collaborative immune responses upon activation. Importantly, peptides derived from previously encountered viral infections can locally reactivate TRM. This biology may have convenient therapeutic ramifications for augmenting tissue-specific immunity. Yet, while TRM have been well-characterized in the gut, skin, and urogenital mucosa, the mouth remains a barrier tissue largely overlooked by T cell biologists. We asked whether TRM in the oral mucosa could be reactivated using virus-mimicking peptides, and if so, how that might impact oral immunity. This question was addressed using a novel prime-pull model for generating preternaturally abundant TRM in the mouths of SPF mice to manipulate and study. Oral TRM reactivation perpetuated a robust oral anti-pathogen state, including induction of key antiviral and interferon-stimulated genes, and recruitment of innate and adaptive cells into the oral mucosa. Oral peptide pre-exposure thwarted infection with an antigenically unrelated virus. Thus, mouth-resident T cells are amenable to local peptide reactivation, and their proinflammatory potential can be intentionally deployed to bolster oral immunity. Supported by T90 DE 022732 K99DE031014 OMIC Pilot Grant
- Published
- 2022
25. Functional virus-specific memory CD8+ T cells survey glioblastoma
- Author
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Pamela Rosato, Jianfang Ning, Noah Veis Gavil, Shaoping Wu, Sathi Wijeyesinghe, Eyob Weyu, Jun Ma, Ming Li, Florina-Nicoleta Grigore, Sanjay Dhawan, Alexander G. Skorput, Shawn C Musial, Sierra A. Kleist, Jordan F. Isaacs, Clark C Chen, and David Masopust
- Subjects
Immunology ,Immunology and Allergy - Abstract
Glioblastoma multiforme (GBM) is among the most aggressive, treatment resistant cancers, and despite standard of care surgery, radiation and chemotherapy, is invariably fatal. GBM is marked by local and systemic immunosuppression, contributing to resistance to existing immunotherapies that have had success in other tumor types. Memory T cells specific for previous infections reside in tissues throughout the host, including the brain, and are capable of rapid and potent immune activation. Here, we show that virus-specific memory CD8+ T cells expressing tissue resident markers populate the mouse and human glioblastoma microenvironment. Reactivating virus-specific memory T cells through intra-tumoral delivery of adjuvant-free virus-derived peptide triggered local immune activation. This delivery translated to anti-neoplastic effects, which improved survival in a murine glioblastoma model. Our results indicate that virus-specific memory T cells are a significant part of the glioblastoma immune microenvironment and may be leveraged to promote anti-tumoral immunity. Supported by UMN SPORE Program Project Planning grant (DM, CCC), NCI 1R01CA238439 (DM), Humor to Fight the Tumor Foundation (JN), NCI 5P30CA023108-42 (PR)
- Published
- 2022
26. Chronic antigen in solid tumors drives a distinct program of T cell residence
- Author
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Noah Veis Gavil, Milcah Scott, Eyob Weyu, Stephen O’flanagan, Sathi Wijeyesinghe, Olivia Smith, and David Masopust
- Subjects
Immunology ,Immunology and Allergy - Abstract
Resident-memory T cells (TRM) permanently reside in tissues, surveying the local environment for cognate antigen. Surrogate markers (e.g. CD69, CD103) and transcriptional programs from infection models are used as correlates of residency. Across numerous solid tumor types, TRM-like phenotypes have been identified and correlated with improved prognosis and responsiveness to immunotherapy. However, the migration properties of CD8+ tumor infiltrating lymphocytes (TILs) have not been well described. In this study, we employed parabiosis migration assays in a mouse model of breast cancer and demonstrated that both virus-specific bystander and tumor-specific CD8+ TILs can be resident. Canonical markers of TRM, including CD69, failed to discriminate between resident cells and recent migrants. However, the expression of markers associated with chronic T cell stimulation (PD-1, CD39, Tim-3) identified a population of resident, tumor-specific cells. We further observed that after tumor entry, Tcf-1+PD-1lo tumor-specific T cells progressively acquired the expression of inhibitory receptors, such as Tim-3, correlating with the phenotypes that represent tumor retention and residence. Thus, TRM exist within tumors, durable intratumoral residence was not informed by common markers associated with pathogen-specific TRM that have been described in healthy tissue, but tumor-specific T cells become resident upon tumor antigen recognition and the subsequent upregulation of CD39 and Tim-3. N.G. is a student in the Medical Scientist Training Program (MD/PhD) at the University of Minnesota and is currently supported through the National Cancer Institute (1F30CA253992-01) with past support from the Dr. Warren J. Warwick and Henrietta Holm Warwick Fellowship. Research supported by the National Cancer Institute (1R01CA238439-01A1, D.M.).
- Published
- 2022
27. Sensing and alarm function of vaccine-elicited SIV-gag specific CD8 TRM in the reproductive mucosa of rhesus macaques
- Author
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Vineet Joag, Clare Quarnstrom, Andrew Soerens, James Michael Stolley, Jason M Schenkel, Kathryn Fraser, Vaiva Vezys, Pamela J Skinner, Eric Hunter, Benjamin Bimber, Rama Rao Amara, and David Masopust
- Subjects
Immunology ,Immunology and Allergy - Abstract
TRM constitute a recently identified lymphocyte lineage that occupies non-lymphoid tissues (NLT) without recirculating. Experiments in mice demonstrated that TRM reactivation triggers antiviral responses in neighboring cells by promoting local stimulation of innate and adaptive immune cells, and by recruiting immune effectors. Collectively this is referred to as ‘sensing and alarm’ function. We wished to broadly identify TRM functions in non-human primates (NHP). Here we applied a prime-boost vaccine modality in rhesus macaques to generate abundant SIVgag-specific CD8 TRM in the female reproductive tract (FRT) and 14 other NLT. To assess sensing and alarm function, macaques were challenged intravaginally with CM9 peptide from the SIV gag protein and necropsied 24 or 48 hours later. CD8 TRM reactivation increased expression of CD69 and granzyme B in SIV-gag specific CD8 T cells throughout the FRT at 24h, in situ proliferation (Ki67 expression) by 48h, and rapid antiviral and IFN response gene expression in essentially all hematopoietic and non-hematopoietic cells by 24h. Upregulation of effector genes in CD8 T cells, CD4 T cells, NK cells, and ILCs peaked at 24h and persisted at 48h. Mucosal CD4 T cells expressed various HIV restriction factors, and had reduced expression of the HIV-coreceptor CCR5. Increased numbers of vaginal T and B cells coincided with increased expression of chemokines and VCAM-1 on endothelial and stromal cells and a concomitant reduction in circulating T cells, B cells and SIV-env-specific B cells. These data demonstrate that vaccine-elicited CD8 TRM rapidly trigger local activation and the recruitment of innate, cellular, and humoral immune responses to the site of antigen exposure.
- Published
- 2022
28. T Cell Memory: Understanding COVID-19
- Author
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Stephen C. Jameson, Nicholas N. Jarjour, and David Masopust
- Subjects
0301 basic medicine ,COVID-19 Vaccines ,Coronavirus disease 2019 (COVID-19) ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,T cell ,viruses ,T-Lymphocytes ,Immunology ,Disease ,Biology ,medicine.disease_cause ,Immunity, Heterologous ,03 medical and health sciences ,0302 clinical medicine ,Immunity ,T-Lymphocyte Subsets ,Pandemic ,medicine ,Immunology and Allergy ,Humans ,skin and connective tissue diseases ,Coronavirus ,B-Lymphocytes ,SARS-CoV-2 ,fungi ,virus diseases ,COVID-19 ,biochemical phenomena, metabolism, and nutrition ,Primer ,Immunity, Innate ,030104 developmental biology ,medicine.anatomical_structure ,Infectious Diseases ,030220 oncology & carcinogenesis ,Neuroscience ,Immunologic memory ,Immunologic Memory - Abstract
As the SARS-CoV-2 pandemic has progressed, increasing attention has focused on establishing natural and vaccine-induced immunity against this coronavirus and the disease, COVID-19, that it causes. In this Primer, we explain the fundamental features of T cell memory and their potential relevance for effective immunity to SARS-CoV-2.
- Published
- 2021
29. Cutting Edge: Mouse SARS-CoV-2 Epitope Reveals Infection and Vaccine-Elicited CD8 T Cell Responses
- Author
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J. Michael Stolley, Peter J. Southern, Siddheshvar Bhela, Thamotharampillai Dileepan, Maxim C.-J. Cheeran, Vineet Joag, Marc K. Jenkins, Sathi Wijeyesinghe, Joshua M. Thiede, Luca Schifanella, Jules A. Sangala, Clare F. Quarnstrom, Geoffrey T. Hart, Stephen D O'Flanagan, Sung-Wook Hong, Venkatramana D. Krishna, William E. Matchett, Noah V. Gavil, David Masopust, Sailaja Gangadhara, Tyler D. Bold, Eyob Weyu, Ryan A. Langlois, Vaiva Vezys, Rama Rao Amara, and Andrew G. Soerens
- Subjects
COVID-19 Vaccines ,T cell ,viruses ,Immunology ,Genetic Vectors ,Heterologous ,Epitopes, T-Lymphocyte ,Mice, Transgenic ,Biology ,CD8-Positive T-Lymphocytes ,Epitope ,Article ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Immunity ,HLA-A2 Antigen ,medicine ,Immunology and Allergy ,Cytotoxic T cell ,Animals ,Coronavirus Nucleocapsid Proteins ,Humans ,Cells, Cultured ,SARS-CoV-2 ,Vaccination ,COVID-19 ,Virology ,Mice, Inbred C57BL ,Disease Models, Animal ,medicine.anatomical_structure ,Immunization ,Humoral immunity ,Female ,Angiotensin-Converting Enzyme 2 ,030215 immunology - Abstract
The magnitude of SARS-CoV-2–specific T cell responses correlates inversely with human disease severity, suggesting T cell involvement in primary control. Whereas many COVID-19 vaccines focus on establishing humoral immunity to viral spike protein, vaccine-elicited T cell immunity may bolster durable protection or cross-reactivity with viral variants. To better enable mechanistic and vaccination studies in mice, we identified a dominant CD8 T cell SARS-CoV-2 nucleoprotein epitope. Infection of human ACE2 transgenic mice with SARS-CoV-2 elicited robust responses to H2-Db/N219-227, and 40% of HLA-A*02+ COVID-19 PBMC samples isolated from hospitalized patients responded to this peptide in culture. In mice, i.m. prime-boost nucleoprotein vaccination with heterologous vectors favored systemic CD8 T cell responses, whereas intranasal boosting favored respiratory immunity. In contrast, a single i.v. immunization with recombinant adenovirus established robust CD8 T cell memory both systemically and in the respiratory mucosa.
- Published
- 2020
30. MO064TISSUE-RESIDENT B CELLS DETERMINE SUSCEPTIBILITY TO URINARY TRACT INFECTION BY ORCHESTRATING MACROPHAGE POLARISATION
- Author
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Trevor D. Lawley, Ondrej Suchanek, Simon Clare, Sathi Wijeyesinghe, Klaus Okkenhaug, John R. Ferdinand, Anita Chandra, David Masopust, Menna R. Clatworthy, Zewen K. Tuong, and Rachael Bashford-Rogers
- Subjects
Transplantation ,Kidney ,Lung ,business.industry ,Urinary system ,Spleen ,medicine.disease ,medicine.disease_cause ,Transplant rejection ,Autoimmunity ,Interleukin 10 ,medicine.anatomical_structure ,Nephrology ,Immunity ,Immunology ,medicine ,business - Abstract
Background Urinary tract infection (UTI) is an important clinical problem. More than half of women and 1 in 10 men will be affected during their lifetime. Many of these affect the lower urinary tract but recurrent pyelonephritis can lead to scarring and chronic kidney disease. There is an increasing appreciation that tissue-resident immune cells, such as macrophages, play an important role in defence against infection, but only little is known about B lymphocytes in this context. Here we sought to address the question of whether B cells reside in the kidney and bladder in homeostasis and to determine their phenotype and contribution to local organ immunity. Methods and Results Using intravenous labelling and parabiosis, we identified a population of bona-fide self-renewing, tissue-resident B cells that included non-naïve and innate-like CD5+ B-1 cells, in murine kidneys and urinary bladder (but also in liver and lung). The size and phenotype of this B cell subset was influenced by genetic background, age, and microbiome, with an expanded population evident after co-housing with pet-store mice. Although kidney B cells had less diverse Igh repertoire compared to blood, their seeding was largely independent of their B-cell receptor specificity. In human kidneys we found a similar enrichment for non-naïve B cells compared to blood and spleen. Using two strains of genetically modified mice with higher (PI3KδE1020K-B) or lower (μMT-) numbers of tissue-resident B cells, we tested the function of these cells during UTI. Surprisingly, the number of tissue-resident B cells inversely correlated with bacterial clearance. We found that these B cells were spatially co-localised with kidney macrophages and skewed their polarization towards an anti-inflammatory M2 phenotype, leading to reduced anti-microbial responses. This effect was, at least in part, driven via IL-10. Conclusion In conclusion, our data identify a critical role for tissue-resident B cells in modulating local immunity in the urinary tract, determining the inflammatory ‘set-point’ of resident and recruited myeloid cells, with important clinical implications for the use of B-cell depleting therapies and conditions such as infection, transplant rejection, fibrosis or autoimmunity. Graphical Abstract
- Published
- 2020
31. Biophysical modeling of the SARS-CoV-2 viral cycle reveals ideal antiviral targets
- Author
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Carissa C. Dock, Ryan A. Langlois, Susan Kline, Christopher J. Tignanelli, Timothy W. Schacker, Mahya Hemmat, Radha Rajasingham, Paolo P. Provenzano, Ashley T. Haase, Brian T. Castle, David J. Odde, and David Masopust
- Subjects
Coronavirus disease 2019 (COVID-19) ,Viral entry ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Model parameters ,Computational biology ,Biology ,Highly sensitive - Abstract
Effective therapies for COVID-19 are urgently needed. Presently there are more than 800 COVID-19 clinical trials globally, many with drug combinations, resulting in an empirical process with an enormous number of possible combinations. To identify the most promising potential therapies, we developed a biophysical model for the SARS-CoV-2 viral cycle and performed a sensitivity analysis for individual model parameters and all possible pairwise parameter changes (162 = 256 possibilities). We found that model-predicted virion production is fairly insensitive to changes in most viral entry, assembly, and release parameters, but highly sensitive to some viral transcription and translation parameters. Furthermore, we found a cooperative benefit to pairwise targeting of transcription and translation, predicting that combined targeting of these processes will be especially effective in inhibiting viral production.
- Published
- 2020
32. Expansible residence decentralizes immune homeostasis
- Author
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J. Michael Stolley, Elizabeth M. Steinert, Omar A. Adam, David Masopust, Lalit K. Beura, Sathi Wijeyesinghe, Mark Pierson, Roland Ruscher, Vaiva Vezys, and Pamela C. Rosato
- Subjects
0301 basic medicine ,Male ,Cellular immunity ,Parabiosis ,Receptors, Antigen, T-Cell ,chemical and pharmacologic phenomena ,Biology ,Adaptive Immunity ,CD8-Positive T-Lymphocytes ,Article ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Immune system ,Immunity ,Animals ,Homeostasis ,Immunologic Surveillance ,Tissue homeostasis ,Multidisciplinary ,Acquired immune system ,Immunity, Innate ,Cell biology ,Mice, Inbred C57BL ,Haematopoiesis ,030104 developmental biology ,Cellular Microenvironment ,Female ,Immunologic Memory ,030215 immunology - Abstract
In metazoans, specific tasks are relegated to dedicated organs that are established early in development, occupy discrete locations and typically remain fixed in size. The adult immune system arises from a centralized haematopoietic niche that maintains self-renewing potential1,2, and—upon maturation—becomes distributed throughout the body to monitor environmental perturbations, regulate tissue homeostasis and mediate organism-wide defence. Here we examine how immunity is integrated within adult mouse tissues, and address issues of durability, expansibility and contributions to organ cellularity. Focusing on antiviral T cell immunity, we observed durable maintenance of resident memory T cells up to 450 days after infection. Once established, resident T cells did not require the T cell receptor for survival or retention of a poised, effector-like state. Although resident memory indefinitely dominated most mucosal organs, surgical separation of parabiotic mice revealed a tissue-resident provenance for blood-borne effector memory T cells, and circulating memory slowly made substantial contributions to tissue immunity in some organs. After serial immunizations or cohousing with pet-shop mice, we found that in most tissues, tissue pliancy (the capacity of tissues to vary their proportion of immune cells) enables the accretion of tissue-resident memory, without axiomatic erosion of pre-existing antiviral T cell immunity. Extending these findings, we demonstrate that tissue residence and organ pliancy are generalizable aspects that underlie homeostasis of innate and adaptive immunity. The immune system grows commensurate with microbial experience, reaching up to 25% of visceral organ cellularity. Regardless of the location, many populations of white blood cells adopted a tissue-residency program within nonlymphoid organs. Thus, residence—rather than renewal or recirculation—typifies nonlymphoid immune surveillance, and organs serve as pliant storage reservoirs that can accommodate continuous expansion of the cellular immune system throughout life. Although haematopoiesis restores some elements of the immune system, nonlymphoid organs sustain an accrual of durable tissue-autonomous cellular immunity that results in progressive decentralization of organismal immune homeostasis. Investigations in mice using parabiosis and cohousing experiments reveal that nonlymphoid organs serve as reservoirs of tissue-autonomous cellular immunity, leading to the decentralization of organism-level immune homeostasis.
- Published
- 2020
33. New Insights into the Immune System Using Dirty Mice
- Author
-
Vladimir P. Badovinac, Lalit K. Beura, Mark Pierson, Thomas S. Griffith, Stephen C. Jameson, David Masopust, and Sara E. Hamilton
- Subjects
Extramural ,Microbiota ,Immunology ,Immunity ,Disease ,Biology ,Article ,Specific Pathogen-Free Organisms ,Translational Research, Biomedical ,Mice ,Immune system ,Genetic similarity ,Models, Animal ,Immunology and Allergy ,Animals ,Neuroscience ,Organism ,Function (biology) - Abstract
The mouse (Mus musculus) is the dominant organism used to investigate the mechanisms behind complex immunological responses because of their genetic similarity to humans and our ability to manipulate those genetics to understand downstream function. Indeed, our knowledge of immune system development, response to infection, and ways to therapeutically manipulate the immune response to combat disease were, in large part, delineated in the mouse. Despite the power of mouse-based immunology research, the translational efficacy of many new therapies from mouse to human is far from ideal. Recent data have highlighted how the naive, neonate-like immune system of specific pathogen–free mice differs dramatically in composition and function to mice living under barrier-free conditions (i.e., “dirty” mice). In this review, we discuss major findings to date and challenges faced when using dirty mice and specific areas of immunology research that may benefit from using animals with robust and varied microbial exposure.
- Published
- 2020
34. Neutrophils Recirculate through Lymph Nodes to Survey Tissues for Pathogens
- Author
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Eugene C. Butcher, Ania Bogoslowski, Christoph Scheiermann, Craig N. Jenne, Paul Kubes, Woo Young Lee, Douglas A. Steeber, Samer Alanani, David Masopust, Chien Sin Chen, and Sathi Wijeyesinghe
- Subjects
Male ,Neutrophils ,Immunology ,High endothelial venules ,Efferent lymphatics ,Population ,ddc:616.07 ,Biology ,Mice ,Immune system ,Venules ,medicine ,Immunology and Allergy ,Animals ,Endothelium ,Lymphocytes ,L-Selectin ,education ,Lymph node ,Sphingosine-1-Phosphate Receptors ,Lymphatic Vessels ,education.field_of_study ,Microbiota ,Staphylococcal Infections ,Mice, Inbred C57BL ,medicine.anatomical_structure ,Lymphatic system ,Neutrophil Infiltration ,Female ,Lymph ,Lymph Nodes ,Neutrophil recruitment - Abstract
The adaptive immune function of lymph nodes is dependent on constant recirculation of lymphocytes. In this article, we identify neutrophils present in the lymph node at steady state, exhibiting the same capacity for recirculation. In germ-free mice, neutrophils still recirculate through lymph nodes, and in mice cohoused with wild microbiome mice, the level of neutrophils in lymph nodes increases significantly. We found that at steady state, neutrophils enter the lymph node entirely via L-selectin and actively exit via efferent lymphatics via an S1P dependent mechanism. The small population of neutrophils in the lymph node can act as reconnaissance cells to recruit additional neutrophils in the event of bacterial dissemination to the lymph node. Without these reconnaissance cells, there is a delay in neutrophil recruitment to the lymph node and a reduction in swarm formation following Staphylococcus aureus infection. This ability to recruit additional neutrophils by lymph node neutrophils is initiated by LTB4. This study establishes the capacity of neutrophils to recirculate, much like lymphocytes via L-selectin and high endothelial venules in lymph nodes and demonstrates how the presence of neutrophils at steady state fortifies the lymph node in case of an infection disseminating through lymphatics.
- Published
- 2020
35. Universal Principled Review: A Community-Driven Method to Improve Peer Review
- Author
-
Matthew Krummel, Catherine Blish, Michael Kuhns, Ken Cadwell, Andrew Oberst, Ananda Goldrath, K. Mark Ansel, Hongbo Chi, Ryan O’Connell, E. John Wherry, Marion Pepper, Igor Brodsky, John Chang, Joseph R. Arron, Nick Haining, Deepta Bhattacharya, Mark Anderson, Carla V. Rothlin, Susan Schwab, Yasmine Belkaid, Ari Molofsky, Pete Savage, Daniel Mucida, Akiko Iwasaki, Gabriel Victora, Jessica Hamerman, David Masopust, Greg Barton, Susan Kaech, Prescott Woodruff, Daniel B. Stetson, Tiffany C. Scharschmidt, Ross Kedl, Elina Isabel Zúñiga, Alexander Hoffmann, Matt Williams, Katrin D. Mayer-Barber, Sunny Shin, Steven Bensinger, Li-Fan Lu, Mark Looney, June L. Round, Sebastian Amigorena, Jonathan Yewdell, Joseph Sun, and John T. Harty
- Subjects
0303 health sciences ,Quality management ,Biomedical Research ,Biology ,Transparency (behavior) ,Data science ,Quality Improvement ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,0302 clinical medicine ,Data quality ,Criticism ,Periodicals as Topic ,030217 neurology & neurosurgery ,030304 developmental biology - Abstract
Despite being a staple of our science, the process of pre-publication peer review has few agreed-upon standards defining its goals or ideal execution. As a community of reviewers and authors, we assembled an evaluation format and associated specific standards for the process as we think it should be practiced. We propose that we apply, debate, and ultimately extend these to improve the transparency of our criticism and the speed with which quality data and ideas become public.
- Published
- 2019
36. Retrograde migration supplies resident memory T cells to lung-draining LN after influenza infection
- Author
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J. Michael Stolley, Jason S. Mitchell, Timothy Johnston, Kevin C. Osum, Sathi Wijeyesinghe, Ryan A. Langlois, Andrew G. Soerens, Pamela C. Rosato, David Masopust, Vineet Joag, and Lalit K. Beura
- Subjects
Male ,T cell ,viruses ,Immunology ,Receptors, Antigen, T-Cell ,Mice, Transgenic ,Biology ,CD8-Positive T-Lymphocytes ,Article ,Infectious Disease and Host Defense ,Mice ,Antigen ,Orthomyxoviridae Infections ,Cell Movement ,medicine ,Immunology and Allergy ,Animals ,Antigens, Viral ,Lung ,CD69 ,T-cell receptor ,Mucosal Immunology ,respiratory system ,Antigens, Differentiation ,respiratory tract diseases ,Granzyme B ,Lymphatic system ,medicine.anatomical_structure ,Influenza A virus ,Female ,Lymph Nodes ,Immunologic Memory ,CD8 - Abstract
Stolley et al. demonstrate that the decay of lung CD8+ T cell responses after primary influenza virus infection is contemporized by the egress of TRM-phenotype T cells from the lung to the draining mediastinal LN by retrograde migration, where they form more stable residents., Numerous observations indicate that resident memory T cells (TRM) undergo unusually rapid attrition within the lung. Here we demonstrate that contraction of lung CD8+ T cell responses after influenza infection is contemporized with egress of CD69+/CD103+ CD8+ T cells to the draining mediastinal LN via the lymphatic vessels, which we term retrograde migration. Cells within the draining LN retained canonical markers of lung TRM, including CD103 and CD69, lacked Ly6C expression (also a feature of lung TRM), maintained granzyme B expression, and did not equilibrate among immunized parabiotic mice. Investigations of bystander infection or removal of the TCR from established memory cells revealed that the induction of the TRM phenotype was dependent on antigen recognition; however, maintenance was independent. Thus, local lung infection induces CD8+ T cells with a TRM phenotype that nevertheless undergo retrograde migration, yet remain durably committed to the residency program within the draining LN, where they provide longer-lived regional memory while chronicling previous upstream antigen experiences., Graphical Abstract
- Published
- 2019
37. Induction of vaginal-resident HIV-specific CD8 T cells with mucosal prime–boost immunization
- Author
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Adam K. Wheatley, R. De Rose, Hyon-Xhi Tan, Robyn Esterbauer, David Masopust, Joshua J. Glass, Sinthujan Jegaskanda, and Stephen J. Kent
- Subjects
0301 basic medicine ,Genetic Vectors ,Immunology ,Immunization, Secondary ,HIV Infections ,Adaptive Immunity ,CD8-Positive T-Lymphocytes ,Biology ,Lymphocyte Activation ,Mice ,03 medical and health sciences ,Immune system ,Cell Movement ,Immunity ,Influenza, Human ,Addressin ,Animals ,Humans ,Immunology and Allergy ,Cytotoxic T cell ,AIDS Vaccines ,Mice, Inbred BALB C ,Mucous Membrane ,Innate immune system ,Acquired immune system ,Virology ,030104 developmental biology ,Immunization ,Organ Specificity ,Vagina ,HIV-1 ,biology.protein ,Female ,Endothelium, Vascular ,Immunologic Memory ,CD8 - Abstract
Tissue-resident memory (TRM) CD8 T cells survey a range of non-lymphoid mucosal tissues where they rapidly mediate clearance of viral infections at the entry portals. Vaccines that establish CD8 TRM cells in the cervicovaginal mucosa hold promise for effective immunity against sexually transmitted HIV. We demonstrate that HIV-specific CD8 TRM cells can be established in the murine vaginal mucosa using a combined intranasal and intravaginal mucosal immunization with recombinant influenza-HIV vectors. Using in situ tetramer immunofluorescence microscopy, we found that this mucosally administered prime-boost immunization also resulted in the durable seeding of CD8 T cells in the frontline vaginal epithelial compartment as opposed to the vaginal submucosa. Upon cognate antigen recognition within the vaginal mucosa, these HIV-specific CD8 TRM cells rapidly initiated a tissue-wide state of immunity. The activation of HIV-specific CD8 TRM cells resulted in the upregulation of endothelial vessel addressin expression and substantial recruitment of both adaptive and innate immune cells in the vaginal mucosa. These findings suggest that the epithelial localization of HIV-specific CD8 TRM cell populations and their capacity to rapidly activate both arms of the immune system could significantly augment frontline defenses against vaginal HIV infection.
- Published
- 2018
38. Understanding Subset Diversity in T Cell Memory
- Author
-
David Masopust and Stephen C. Jameson
- Subjects
Epigenomics ,0301 basic medicine ,Protective immunity ,media_common.quotation_subject ,T cell ,Immunology ,Population ,Biology ,Article ,03 medical and health sciences ,0302 clinical medicine ,Cell Movement ,T-Lymphocyte Subsets ,medicine ,Animals ,Humans ,Immunology and Allergy ,education ,media_common ,education.field_of_study ,Longevity ,Cell Differentiation ,Cell movement ,030104 developmental biology ,Infectious Diseases ,medicine.anatomical_structure ,Immunologic Memory ,Neuroscience ,030215 immunology - Abstract
Considerable advances have been made in recent years in understanding the generation and function of memory T cells. Memory T cells are typically parsed into discreet subsets based on phenotypic definitions that connote distinct roles in immunity. Here we consider new developments in the field and focus on how emerging differences between memory cells with respect to their trafficking, metabolism, epigenetic regulation, and longevity may fail to fit into small groups of "memory subsets." Rather, the properties of individual memory T cells fall on a continuum within each of these and other parameters. We discuss how this continuum influences the way that the efficacy of vaccination is assessed, as well as the suitability of a memory population for protective immunity.
- Published
- 2018
39. Mice with diverse microbial exposure histories as a model for preclinical vaccine testing
- Author
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David K. Meyerholz, J. Michael Stolley, Hezkiel Nanda, Clayton K. Mickelson, Frances K. Shepherd, Sathi Wijeyesinghe, Vaiva Vezys, Sara E. Hamilton, Mark Pierson, Steven S. Shen, Ryan A. Langlois, Jessica K. Fiege, David Masopust, Katharine E. Block, and William E. Matchett
- Subjects
Male ,Mice, Inbred BALB C ,Vaccination ,Biology ,Microbiology ,Immunity, Humoral ,Mice, Inbred C57BL ,Mice ,Immunogenicity, Vaccine ,Immune system ,Vaccine Immunogenicity ,Poor control ,Influenza Vaccines ,Immunity ,Virology ,Immunology ,Humoral immunity ,Post vaccination ,Vaccine Testing ,Animals ,Humans ,Female ,Parasitology ,Spotlight - Abstract
Summary In a recent issue of Cell Host and Microbe, Fiege and colleagues1 report that laboratory mice exposed to pathogens from pet-store mice exhibit impaired humoral immunity to influenza vaccination and display gene expression signatures that more authentically reflect human vaccine responses., In a recent issue of Cell Host and Microbe, Fiege and colleagues1 report that laboratory mice exposed to pathogens from pet-store mice exhibit impaired humoral immunity to influenza vaccination and display gene expression signatures that more authentically reflect human vaccine responses.
- Published
- 2021
40. Validating cell surface markers as accurate predictors of tissue residency
- Author
-
Milcah C Scott, J. Michael Stolley, Mark J Pierson, Sathi Wijeyesinghe, Noah Veis Gavil, and David Masopust
- Subjects
Immunology ,Immunology and Allergy - Abstract
Tissue resident memory T cells (TRM) represent the dominant antigen-experienced T cell subset that mediate local immunosurveillance in non-lymphoid tissues (NLT). Most accurately defined using migration assays, including parabiosis surgery and tissue grafting, TRM remain situated within NLT without recirculating through the blood. Such migration assays are challenging and often impossible to perform given animal-use approval or experimental constraints. These limitations have necessitated the use of cell surface markers such as CD69 and CD103 as surrogates for residency in the absence of more stringent approaches. Yet reliance on these cell surface markers alone often fails to accurately predict residency in tissues. As such, we performed a systematic interrogation of the correlation between flow cytometric staining profiles and the property of durable residence as assessed using parabiosis. In multiple infection models, we found that no consistent marker combination accurately identifies and captures the abundance and heterogeneity of TRM in diverse NLT. By evaluating the usefulness of cell surface markers as diagnostic of residency on a tissue- and infection-specific basis, we identified tissue specific phenotypes that reproducibly predicted residency in three infection models. These findings are important because refined analyses of TRM populations is key to addressing deficiencies in our understanding of how TRM mediate immunosurveillance. Ongoing work will further validate these tissue-specific phenotypes in additional infection models and ‘dirty mice’ that contain CD69+ T cells within the equilibrating T cell populations.
- Published
- 2021
41. Generation and implications of oral resident memory T cells
- Author
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J. Michael Stolley and David Masopust
- Subjects
Immunology ,Immunology and Allergy - Abstract
CD8+ tissue resident memory T cells (TRM) represent the predominant memory T cell population in many nonlymphoid tissues (NLT) where they are major contributors to localized immunosurveillance. TRM accelerate protection against reinfection, may be associated with tumor control, and may also facilitate the persistence of certain allergic and autoimmune diseases. While extensively studied in other mucosal sites, there is presently a fundamental void in our understanding of the ontogeny, function, and therapeutic implications of oral-mucosal TRM. Given their well-documented and critical functions in mediating barrier immunosurveillance in other NLT, oral TRM are likely to play a major role in antiviral immunity and oral immune homeostasis. TRM may also perpetuate chronic immune responses observed in periodontal disease and oral lichen planus. However, addressing their role in these clinically relevant settings has been mired by a lack of animal models for generating sufficient oral TRM to manipulate and study. Here we introduce a novel oral ‘prime-pull’ strategy for generating large quantities of tractable TRM of a defined antigen specificity within the oral mucosa. Leveraging this approach, we demonstrate that oral TRM 1) are abundant within mouse gingiva, 2) are intimately associated with salivary ducts of the tongue and buccal mucosa, and 3) can be locally reactivated to potentiate oral immunity. Ongoing work will further define the tissue-specific functions of oral TRM and describe new mechanisms by which oral immunity can be attenuated or augmented to achieve the desired clinical outcome.
- Published
- 2021
42. Tumor-infiltrating CD8+ T cells can be resident, but exhaustion markers rather than CD69 correlate with residence and tumor specificity
- Author
-
Noah Veis Gavil, Eyob Weyu, Milcah C. Scott, Olivia Smith, Sathi Wijeyesinghe, and David Masopust
- Subjects
Immunology ,Immunology and Allergy - Abstract
Tumor infiltrating lymphocytes (TILs) represent a heterogeneous population of both pathogen-specific bystander and tumor-specific CD8+ T cells. Within select solid tumors, the expression of exhaustion markers PD-1 and CD39 has been used to discriminate between pathogen-specific and tumor-specific cells. Independent studies across numerous types of solid tumors have also shown that CD8+ TILs can exhibit distinct signatures that imply residence, however, the migrational properties of TILs have not been fully elucidated. In this study, we employed parabiosis migration assays in a mouse model of breast cancer and demonstrated that both virus-specific bystander and tumor-specific CD8+ T cells within the tumor microenvironment (TME) can be resident. Canonical markers of resident-memory T cells (TRM), including CD69, failed to discriminate between resident cells and recent migrants. However, the expression of markers associated with T cell dysfunction (PD-1, CD39, Tim-3, Lag-3) identified a population of tumor-specific cells and was tightly correlated with residence within the TME. Thus, TRM exist within tumors, durable intratumoral residence was not well informed by common markers associated with TRM in healthy tissues, and the expression of exhaustion markers correlated with both tumor specificity and durable residence.
- Published
- 2021
43. Tissue resident memory T cells and viral immunity
- Author
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Lalit K. Beura, Pamela C. Rosato, and David Masopust
- Subjects
0301 basic medicine ,Extramural ,Effector ,T cell ,Viral challenge ,CD8-Positive T-Lymphocytes ,Biology ,Virology ,Article ,03 medical and health sciences ,030104 developmental biology ,Immune system ,medicine.anatomical_structure ,T-Lymphocyte Subsets ,Virus Diseases ,Immunity ,Immunology ,medicine ,Animals ,Humans ,Immunologic Memory ,Immunologic memory - Abstract
Tissue resident memory T cells (TRM) constitute a recently identified T cell lineage that is responsible for frontline defense against viral infections. In contrast to central and effector memory T cells, which constitutively recirculate between tissues and blood, TRM reside permanently within tissues. As the main surveyors of non-lymphoid tissues, TRM are positioned to rapidly respond upon reinfection at barrier sites. During a viral reinfection, TRM trigger the local tissue environment to activate and recruit immune cells and establish an antiviral state. Consistent with this function, there is empirical evidence that TRM accelerate control in the event of reinfection or possible reactivation of latent infections in solid organs and barrier tissues. Here we review recent literature highlighting the protective functions of TRM in multiple viral challenge models and contextualize the implications of these findings for vaccine development.
- Published
- 2017
44. Developmental plasticity allows outside-in immune responses by resident memory T cells
- Author
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Nancy J. Fares-Frederickson, Vaiva Vezys, Emily A. Thompson, Henrique Borges da Silva, Sathi Wijeyesinghe, Caitlin C. Zebley, Clare F. Quarnstrom, Hazem E. Ghoneim, Lalit K. Beura, Raissa Fonseca, David Masopust, Yiping Fan, Benjamin Youngblood, and Milcah C. Scott
- Subjects
0301 basic medicine ,T cell ,Cellular differentiation ,Immunology ,Cell Plasticity ,Biology ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Immune system ,Intestinal mucosa ,T-Lymphocyte Subsets ,Intestine, Small ,medicine ,Immunology and Allergy ,Animals ,Epigenetics ,Intestinal Mucosa ,Effector ,Cell Differentiation ,Cell biology ,Mice, Inbred C57BL ,030104 developmental biology ,medicine.anatomical_structure ,Female ,Immunologic Memory ,030215 immunology ,Homing (hematopoietic) - Abstract
Central memory T (TCM) cells patrol lymph nodes and perform conventional memory responses on restimulation: proliferation, migration and differentiation into diverse T cell subsets while also self-renewing. Resident memory T (TRM) cells are parked within single organs, share properties with terminal effectors and contribute to rapid host protection. We observed that reactivated TRM cells rejoined the circulating pool. Epigenetic analyses revealed that TRM cells align closely with conventional memory T cell populations, bearing little resemblance to recently activated effectors. Fully differentiated TRM cells isolated from small intestine epithelium exhibited the potential to differentiate into TCM cells, effector memory T cells and TRM cells on recall. Ex-TRM cells, former intestinal TRM cells that rejoined the circulating pool, heritably maintained a predilection for homing back to their tissue of origin on subsequent reactivation and a heightened capacity to redifferentiate into TRM cells. Thus, TRM cells can rejoin the circulation but are advantaged to re-form local TRM when called on.
- Published
- 2019
45. Virus-specific memory T cells populate tumors and can be repurposed for tumor immunotherapy
- Author
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Luke S. Manlove, J. Michael Stolley, Christine E. Nelson, Vaiva Vezys, Pamela C. Rosato, Bruce R. Blazar, David Masopust, Christopher A. Pennell, Rachel L. Davis, Melissa A. Geller, Clark C. Chen, and Sathi Wijeyesinghe
- Subjects
Male ,0301 basic medicine ,medicine.medical_treatment ,General Physics and Astronomy ,02 engineering and technology ,CD8-Positive T-Lymphocytes ,Mice ,Cancer immunotherapy ,Neoplasms ,Tumor Microenvironment ,Cytotoxic T cell ,Child ,lcsh:Science ,Aged, 80 and over ,Multidisciplinary ,Middle Aged ,021001 nanoscience & nanotechnology ,Acquired immune system ,Female ,Immunotherapy ,0210 nano-technology ,Adult ,Adolescent ,Science ,Antigen presentation ,Biology ,Article ,General Biochemistry, Genetics and Molecular Biology ,Young Adult ,03 medical and health sciences ,Antigen ,Antigens, Neoplasm ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Aged ,Tumor microenvironment ,General Chemistry ,biochemical phenomena, metabolism, and nutrition ,Mice, Inbred C57BL ,030104 developmental biology ,Microscopy, Fluorescence ,Cancer research ,bacteria ,lcsh:Q ,CD8 ,T-Lymphocytes, Cytotoxic - Abstract
The immunosuppressive tumor microenvironment limits the success of current immunotherapies. The host retains memory T cells specific for previous infections throughout the entire body that are capable of executing potent and immediate immunostimulatory functions. Here we show that virus-specific memory T cells extend their surveillance to mouse and human tumors. Reactivating these antiviral T cells can arrest growth of checkpoint blockade-resistant and poorly immunogenic tumors in mice after injecting adjuvant-free non-replicating viral peptides into tumors. Peptide mimics a viral reinfection event to memory CD8+ T cells, triggering antigen presentation and cytotoxic pathways within the tumor, activating dendritic cells and natural killer cells, and recruiting the adaptive immune system. Viral peptide treatment of ex vivo human tumors recapitulates immune activation gene expression profiles observed in mice. Lastly, peptide therapy renders resistant mouse tumors susceptible to PD-L1 blockade. Thus, re-stimulating known antiviral immunity may provide a unique therapeutic approach for cancer immunotherapy., The immunosuppressive tumor environment and the lack of functional anti-tumor immunity are major limiting factors in immunotherapy. Here the authors show that human and mouse tumors are infiltrated by virus-specific memory T cells, which can be harnessed by viral peptides to induce local and systemic anti-tumor immunity and synergize with checkpoint blockade.
- Published
- 2019
46. Vaccine induction of antibodies and tissue-resident CD8+ T cells enhances protection against mucosal SHIV-infection in young macaques
- Author
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John P. Vasilakos, Rafiq Nabi, Dan H. Barouch, Yevgeniy Kovalenkov, Sudhir Pai Kasturi, Pamela A. Kozlowski, Traci Legere, Bali Pulendran, Jonathan W. Yewdell, David C. Montefiori, Jens Wrammert, James S. Gibbs, Parin Patel, Lori M. Spicer, Mark A. Tomai, Pradeep B. J. Reddy, Eric Hunter, Barton F. Haynes, C. Yong Kang, Clare F. Quarnstrom, David Masopust, Caroline Petitdemange, Cynthia A. Derdeyn, Celia C. LaBranche, Francois Villinger, and Rama Rao Amara
- Subjects
0301 basic medicine ,T cell ,viruses ,Genetic Vectors ,Simian Acquired Immunodeficiency Syndrome ,HIV Infections ,Biology ,CD8-Positive T-Lymphocytes ,Antibodies, Viral ,03 medical and health sciences ,0302 clinical medicine ,Immunogenicity, Vaccine ,Adjuvants, Immunologic ,medicine ,Cytotoxic T cell ,Animals ,AIDS Vaccines ,Vaccines, Synthetic ,Mucous Membrane ,Vaccination ,Antibody titer ,env Gene Products, Human Immunodeficiency Virus ,General Medicine ,Acquired immune system ,biology.organism_classification ,Virology ,Antibodies, Neutralizing ,Macaca mulatta ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,Treatment Outcome ,Immunization ,Vesicular stomatitis virus ,030220 oncology & carcinogenesis ,Vagina ,biology.protein ,HIV-1 ,Female ,Simian Immunodeficiency Virus ,Antibody ,Heterocyclic Compounds, 3-Ring ,CD8 ,Stearic Acids ,Research Article - Abstract
Antibodies and cytotoxic T cells represent 2 arms of host defense against pathogens. We hypothesized that vaccines that induce both high-magnitude CD8(+) T cell responses and antibody responses might confer enhanced protection against HIV. To test this hypothesis, we immunized 3 groups of nonhuman primates: (a) Group 1, which includes sequential immunization regimen involving heterologous viral vectors (HVVs) comprising vesicular stomatitis virus, vaccinia virus, and adenovirus serotype 5–expressing SIVmac239 Gag; (b) Group 2, which includes immunization with a clade C HIV-1 envelope (Env) gp140 protein adjuvanted with nanoparticles containing a TLR7/8 agonist (3M-052); and (c) Group 3, which includes a combination of both regimens. Immunization with HVVs induced very high–magnitude Gag-specific CD8(+) T cell responses in blood and tissue-resident CD8(+) memory T cells in vaginal mucosa. Immunization with 3M-052 adjuvanted Env protein induced robust and persistent antibody responses and long-lasting innate responses. Despite similar antibody titers in Groups 2 and 3, there was enhanced protection in the younger animals in Group 3, against intravaginal infection with a heterologous SHIV strain. This protection correlated with the magnitude of the serum and vaginal Env-specific antibody titers on the day of challenge. Thus, vaccination strategies that induce both CD8(+) T cell and antibody responses can confer enhanced protection against infection.
- Published
- 2018
47. Competition for Active TGFβ Cytokine Allows for Selective Retention of Antigen-Specific Tissue- Resident Memory T Cells in the Epidermal Niche
- Author
-
Dario A. A. Vignali, David W. Griggs, Daniel H. Kaplan, Haiyue Li, Creg J. Workman, Yi Yang, Toshiro Hirai, Yukari Zenke, David Masopust, Breanna Anh Thu Nguyen, Harinder Singh, Laurent Bartholin, Jacinto S. De La Cruz Diaz, Virendra K. Chaudhri, and Paul Yifan Zhou
- Subjects
Keratinocytes ,0301 basic medicine ,Receptors, Antigen, T-Cell, alpha-beta ,medicine.medical_treatment ,Immunology ,T-Cell Antigen Receptor Specificity ,CD8-Positive T-Lymphocytes ,Biology ,Binding, Competitive ,T-Lymphocytes, Regulatory ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Antigen ,Transforming Growth Factor beta ,medicine ,Bystander effect ,Animals ,Immunology and Allergy ,Autocrine signalling ,Lymph node ,integumentary system ,Epidermis (botany) ,Bystander Effect ,Clone Cells ,Cell biology ,Mice, Inbred C57BL ,030104 developmental biology ,Infectious Diseases ,Cytokine ,medicine.anatomical_structure ,Cellular Microenvironment ,Organ Specificity ,030220 oncology & carcinogenesis ,Epidermis ,Immunologic Memory ,CD8 ,Signal Transduction ,Transforming growth factor - Abstract
Summary Following antigen-driven expansion in lymph node, transforming growth factor-β (TGFβ) is required for differentiation of skin-recruited CD8+ T cell effectors into epidermal resident memory T (Trm) cells and their epidermal persistence. We found that the source of TGFβ -supporting Trm cells was autocrine. In addition, antigen-specific Trm cells that encountered cognate antigen in the skin, and bystander Trm cells that did not, both displayed long-term persistence in the epidermis under steady-state conditions. However, when the active-TGFβ was limited or when new T cell clones were recruited into the epidermis, antigen-specific Trm cells were more efficiently retained than bystander Trm cells. Genetically enforced TGFβR signaling allowed bystander Trm cells to persist in the epidermis as efficiently as antigen-specific Trm cells in both contexts. Thus, competition between T cells for active TGFβ represents an unappreciated selective pressure that promotes the accumulation and persistence of antigen-specific Trm cells in the epidermal niche.
- Published
- 2021
48. Normalizing the environment recapitulates adult human immune traits in laboratory mice
- Author
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Kathryn A. Fraser, Sara E. Hamilton, Marc K. Jenkins, Pamela C. Rosato, Emily A. Thompson, Oludare A. Odumade, Kerry A. Casey, Vaiva Vezys, Kevin Bi, W. Nicholas Haining, Jason M. Schenkel, Ali Filali-Mouhim, Rafick Pierre Sekaly, David Masopust, Lalit K. Beura, and Stephen C. Jameson
- Subjects
0301 basic medicine ,Multidisciplinary ,Cellular differentiation ,Laboratory mouse ,Environmental exposure ,Biology ,Blood cell ,03 medical and health sciences ,030104 developmental biology ,medicine.anatomical_structure ,Immune system ,Immunity ,Immunology ,medicine ,Specific Pathogen Free Organism ,Specific-pathogen-free - Abstract
Our current understanding of immunology was largely defined in laboratory mice, partly because they are inbred and genetically homogeneous, can be genetically manipulated, allow kinetic tissue analyses to be carried out from the onset of disease, and permit the use of tractable disease models. Comparably reductionist experiments are neither technically nor ethically possible in humans. However, there is growing concern that laboratory mice do not reflect relevant aspects of the human immune system, which may account for failures to translate disease treatments from bench to bedside. Laboratory mice live in abnormally hygienic specific pathogen free (SPF) barrier facilities. Here we show that standard laboratory mouse husbandry has profound effects on the immune system and that environmental changes produce mice with immune systems closer to those of adult humans. Laboratory mice--like newborn, but not adult, humans--lack effector-differentiated and mucosally distributed memory T cells. These cell populations were present in free-living barn populations of feral mice and pet store mice with diverse microbial experience, and were induced in laboratory mice after co-housing with pet store mice, suggesting that the environment is involved in the induction of these cells. Altering the living conditions of mice profoundly affected the cellular composition of the innate and adaptive immune systems, resulted in global changes in blood cell gene expression to patterns that more closely reflected the immune signatures of adult humans rather than neonates, altered resistance to infection, and influenced T-cell differentiation in response to a de novo viral infection. These data highlight the effects of environment on the basal immune state and response to infection and suggest that restoring physiological microbial exposure in laboratory mice could provide a relevant tool for modelling immunological events in free-living organisms, including humans.
- Published
- 2016
49. Stromal cells control the epithelial residence of DCs and memory T cells by regulated activation of TGF-β
- Author
-
Brian Chicoine, David Masopust, Sakeen W. Kashem, Laurent Bartholin, Sathi Wijeyesinghe, Alesia Kaplan, Nathan E. Welty, Alina G. Bridges, Emily A. Thompson, Botond Z. Igyártó, Warren D. Shlomchik, Brian Astry, Daniel H. Kaplan, Aleh Bobr, Lalit K. Beura, Catherine C. Matte, Dean Sheppard, Javed Mohammed, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université Claude Bernard Lyon 1 ( UCBL ), and Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS )
- Subjects
Keratinocytes ,0301 basic medicine ,Integrins ,T-Lymphocytes ,Fluorescent Antibody Technique ,Growth ,CD8-Positive T-Lymphocytes ,Polymerase Chain Reaction ,Epithelium ,[ SDV.CAN ] Life Sciences [q-bio]/Cancer ,Mice ,0302 clinical medicine ,Cell Movement ,T-Lymphocyte Subsets ,Transforming Growth Factor beta ,Intestine, Small ,Immunology and Allergy ,Intestinal Mucosa ,Skin ,Mice, Knockout ,integumentary system ,medicine.diagnostic_test ,Flow Cytometry ,Cell biology ,Medicine ,France ,Stromal cell ,Cells ,Immunology ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Dermatology ,Biology ,Article ,Flow cytometry ,Transforming Growth Factor beta1 ,03 medical and health sciences ,Immune system ,Antigen ,Antigens, Neoplasm ,medicine ,Animals ,Humans ,Immunity, Mucosal ,Epidermis (botany) ,microbiology ,Dendritic Cells ,Transforming growth factor beta ,030104 developmental biology ,Epidermal Cells ,Mink ,Langerhans Cells ,Immune System ,biology.protein ,pathology ,Epidermis ,Stromal Cells ,Laboratories ,CD8 ,030215 immunology ,Transforming growth factor - Abstract
International audience; Cells of the immune system that reside in barrier epithelia provide a first line of defense against pathogens. Langerhans cells (LCs) and CD8+ tissue-resident memory T cells (TRM cells) require active transforming growth factor-beta1 (TGF-beta) for epidermal residence. Here we found that integrins alphavbeta6 and alphavbeta8 were expressed in non-overlapping patterns by keratinocytes (KCs) and maintained the epidermal residence of LCs and TRM cells by activating latent TGF-beta. Similarly, the residence of dendritic cells and TRM cells in the small intestine epithelium also required alphavbeta6. Treatment of the skin with ultraviolet irradiation decreased integrin expression on KCs and reduced the availability of active TGF-beta, which resulted in LC migration. Our data demonstrated that regulated activation of TGF-beta by stromal cells was able to directly control epithelial residence of cells of the immune system through a novel mechanism of intercellular communication
- Published
- 2016
50. CD8 T cell immunosurveillance and elimination of HIV target cells in the female reproductive tract
- Author
-
Vineet Joag, Jason Mitchell, Brian T Fife, and David Masopust
- Subjects
Immunology ,Immunology and Allergy - Abstract
HIV infection is thought to establish in a single founder CD4 T cell in the genital mucosa, however, an effective CD8 T cell-based vaccine must enable timely surveillance of all mucosal CD4 T cells within the first few days after HIV exposure. The HVTN 502 (STEP) vaccine trial employed a CD8 T cell based vaccine that while promising in animal studies, did not protect human vaccinees from mucosal HIV acquisition. We hypothesize that the quantity of mucosal HIV-specific CD8 T cells is a critical determinant of tissue immunosurveillance and was insufficient to adequately survey and eliminate HIV target cells in the STEP trial. To test our hypothesis, we applied intravital mucosal imaging to visualize how efficiently CD8 T cells survey CD4 T cells in the murine uterus. Based on CD8-CD4 T cell contact rates, a density of 4 (0.8%) HIV-specific mucosal CD8 T cells/mm2 would be required to survey all mucosal CD4 T cells within 2 days. However, vaccinees in the STEP trial had ELISPOT readings of ≥55 spot-forming units/106 blood leucocytes or approximately 0.09% mucosal HIV-specific CD8 T cells, which is 10 fold lower than the required density. Surveillance efficiency was directly correlated with the number of CD8 T cells and was independent of target cell numbers. Upon antigen recognition in the context of MHC-I on CD4 T cells, CD8 T cells formed kinapses with CD4 T cells in an LFA-1/ICAM-1 dependent manner, facilitating tethering and prolonged tracking. Direct killing of CD4 T cells by single or multiple CD8 T cells occurred by 3h after antigen presentation. We conclude that CD8 T cells are capable of rapid tissue surveillance and killing of CD4 T cell targets, and that sub-optimal numbers of HIV-specific CD8 T cells may have contributed to the failure of the STEP trial.
- Published
- 2020
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