113 results on '"Barber, Daniel L."'
Search Results
2. BACH1 promotes tissue necrosis and Mycobacterium tuberculosis susceptibility
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Amaral, Eduardo P., Namasivayam, Sivaranjani, Queiroz, Artur T. L., Fukutani, Eduardo, Hilligan, Kerry L., Aberman, Kate, Fisher, Logan, Bomfim, Caio Cesar B., Kauffman, Keith, Buchanan, Jay, Santuo, Leslie, Gazzinelli-Guimaraes, Pedro Henrique, Costa, Diego L., Teixeira, Mariane Araujo, Barreto-Duarte, Beatriz, Rocha, Clarissa Gurgel, Santana, Monique Freire, Cordeiro-Santos, Marcelo, Barber, Daniel L., Wilkinson, Robert J., Kramnik, Igor, Igarashi, Kazuhiko, Scriba, Thomas, Mayer-Barber, Katrin D., Andrade, Bruno B., and Sher, Alan
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- 2024
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3. Rapid pathogen-specific recruitment of immune effector cells in the skin by secreted toxins
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Nguyen, Thuan H., Cheung, Gordon Y. C., Rigby, Kevin M., Kamenyeva, Olena, Kabat, Juraj, Sturdevant, Daniel E., Villaruz, Amer E., Liu, Ryan, Piewngam, Pipat, Porter, Adeline R., Firdous, Saba, Chiou, Janice, Park, Matthew D., Hunt, Rachelle L., Almufarriji, Fawaz M. F., Tan, Vee Y., Asiamah, Titus K., McCausland, Joshua W., Fisher, Emilie L., Yeh, Anthony J., Bae, Justin S., Kobayashi, Scott D., Wang, Ji Ming, Barber, Daniel L., DeLeo, Frank R., and Otto, Michael
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- 2022
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4. Mycobacterium tuberculosis-specific CD4 T cells expressing CD153 inversely associate with bacterial load and disease severity in human tuberculosis
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Du Bruyn, Elsa, Ruzive, Sheena, Lindestam Arlehamn, Cecilia S., Sette, Alessandro, Sher, Alan, Barber, Daniel L., Wilkinson, Robert J., and Riou, Catherine
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- 2021
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5. Exacerbation of CMV and Nontuberculous Mycobacterial Infections Following PD-1 Blockade for HIV-Associated Kaposi Sarcoma.
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Anidi, Ifeanyichukwu U, Sakai, Shunsuke, Brooks, Kelsie, Fling, Steven P, Wagner, Michael J, Lurain, Kathryn, Arlehamn, Cecilia S Lindestam, Sette, Alessandro, Knox, Kenneth S, Brenchley, Jason M, Uldrick, Thomas S, Sharon, Elad, and Barber, Daniel L
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MYCOBACTERIAL diseases ,KAPOSI'S sarcoma ,PROGRAMMED cell death 1 receptors ,LYMPHADENITIS ,T cells ,DISEASE exacerbation - Abstract
Blockade of the co-inhibitory receptor PD-1 enhances antitumor responses by boosting the function of antigen-specific T cells. Although rare, PD-1 blockade in patients with cancer can lead to exacerbation of infection-associated pathology. Here, we detail the case of a 38-year-old man who was enrolled in a clinical trial for assessment of the safety and activity of anti–PD-1 therapy for Kaposi sarcoma in people with HIV well-controlled on antiretroviral therapy. Less than a week after receiving the first dose of anti–PD-1 antibody (pembrolizumab), he presented with severe abdominal pain associated with sudden exacerbations of preexisting cytomegalovirus (CMV) enteritis and nontuberculous mycobacterial mesenteric lymphadenitis. Plasma biomarkers of gastrointestinal tract damage were highly elevated compared with healthy controls, consistent with HIV-associated loss of gut epithelial barrier integrity. Moreover, CMV-specific CD8 T cells expressed high levels of PD-1, and 7 days following PD-1 blockade, there was an increase in the frequency of activated CD38
+ Ki67+ CMV-specific CD8 T cells. This case highlights the potential for PD-1 blockade to drive rapid exacerbations of inflammatory symptoms when administered to individuals harboring multiple unresolved infections. [ABSTRACT FROM AUTHOR]- Published
- 2024
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6. MAIT cell-directed therapy of Mycobacterium tuberculosis infection
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Sakai, Shunsuke, Kauffman, Keith D., Oh, Sangmi, Nelson, Christine E., Barry, III, Clifton E., and Barber, Daniel L.
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- 2021
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7. Migration-induced cell shattering due to DOCK8 deficiency causes a type 2–biased helper T cell response
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Schneider, Caitlin, Shen, Connie, Gopal, Angelica A., Douglas, Todd, Forestell, Benjamin, Kauffman, Keith D., Rogers, Dakota, Artusa, Patricio, Zhang, Qian, Jing, Huie, Freeman, Alexandra F., Barber, Daniel L., King, Irah L., Saleh, Maya, Wiseman, Paul W., Su, Helen C., and Mandl, Judith N.
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- 2020
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8. Host resistance to pulmonary Mycobacterium tuberculosis infection requires CD153 expression
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Sallin, Michelle A., Kauffman, Keith D., Riou, Catherine, Du Bruyn, Elsa, Foreman, Taylor W., Sakai, Shunsuke, Hoft, Stella G., Myers, Timothy G., Gardina, Paul J., Sher, Alan, Moore, Rashida, Wilder-Kofie, Temeri, Moore, Ian N., Sette, Alessandro, Lindestam Arlehamn, Cecilia S., Wilkinson, Robert J., and Barber, Daniel L.
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- 2018
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9. Antigen-Independent Memory CD8 T Cells Do Not Develop during Chronic Viral Infection
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Wherry, E. John, Barber, Daniel L., Kaech, Susan M., Blattman, Joseph N., Ahmed, Rafi, and Marrack, Philippa
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- 2004
10. Lethal CD4 T Cell Responses Induced by Vaccination Against Staphylococcus aureus Bacteremia
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Karauzum, Hatice, Haudenschild, Christian C., Moore, Ian N., Mahmoudieh, Mahta, Barber, Daniel L., and Datta, Sandip K.
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- 2017
11. Rescue of exhausted CD8 T cells by PD-1–targeted therapies is CD28-dependent
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Kamphorst, Alice O., Wieland, Andreas, Nasti, Tahseen, Yang, Shu, Zhang, Ruan, Barber, Daniel L., Konieczny, Bogumila T., Daugherty, Candace Z., Koenig, Lydia, Yu, Ke, Sica, Gabriel L., Sharpe, Arlene H., Freeman, Gordon J., Blazar, Bruce R., Turka, Laurence A., Owonikoko, Taofeek K., Pillai, Rathi N., Ramalingam, Suresh S., Araki, Koichi, and Ahmed, Rafi
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- 2017
12. Severe Paradoxical Reaction During Treatment of Disseminated Tuberculosis in a Patient With Neutralizing Anti-IFNγ Autoantibodies
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Xie, Yingda L., Rosen, Lindsey B., Sereti, Irini, Barber, Daniel L., Chen, Ray Y., Hsu, Denise C., Qasba, S. Sonia, Zerbe, Christa S., Holland, Steven M., and Browne, Sarah K.
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- 2016
13. Blood and Site of Disease Inflammatory Profiles Differ in Patients With Pericardial Tuberculosis and Human Immunodeficiency Virus Type 1.
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Mutavhatsindi, Hygon, Bruyn, Elsa Du, Ruzive, Sheena, Howlett, Patrick, Cerrone, Maddalena, Sher, Alan, Mayer-Barber, Katrin D, Barber, Daniel L, Ntsekhe, Mpiko, Wilkinson, Robert J, and Riou, Catherine
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Background To better understand the pathogenesis of pericardial tuberculosis (PCTB), we sought to characterize the systemic inflammatory profile in people with human immunodeficiency virus type 1 (HIV-1) with latent TB infection (LTBI), pulmonary TB (PTB), or PCTB. Methods Using Luminex, we measured the concentration of 39 analytes in pericardial fluid (PCF) and paired plasma from 18 PCTB participants, and plasma from 16 LTBI and 20 PTB participants. Follow-up plasma samples were also obtained from PTB and PCTB participants. HLA-DR expression on Mycobacterium tuberculosis –specific CD4 T cells was measured in baseline samples using flow cytometry. Results Assessment of the overall systemic inflammatory profile by principal component analysis showed that the inflammatory profile of active TB participants was distinct from the LTBI group, while PTB patients could not be distinguished from those with PCTB. When comparing the inflammatory profile between PCF and paired blood, we found that the concentrations of most analytes (25/39) were elevated at site of disease. However, the inflammatory profile in PCF partially mirrored inflammatory events in the blood. After TB treatment completion, the overall plasma inflammatory profile reverted to that observed in the LTBI group. Lastly, HLA-DR expression showed the best performance for TB diagnosis compared to previously described biosignatures built from soluble markers. Conclusions Our results show that the inflammatory profile in blood was comparable between PTB and PCTB. However, at the site of infection (PCF), inflammation was significantly elevated compared to blood. Additionally, our data emphasize the potential role of HLA-DR expression as a biomarker for TB diagnosis. [ABSTRACT FROM AUTHOR]
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- 2023
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14. Induction of Inhibitory Receptors on T Cells During Plasmodium vivax Malaria Impairs Cytokine Production
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Costa, Pedro A. C., Leoratti, Fabiana M. S., Figueiredo, Maria M., Tada, Mauro S., Pereira, Dhelio B., Junqueira, Caroline, Soares, Irene S., Barber, Daniel L., Gazzinelli, Ricardo T., and Antonelli, Lis R. V.
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- 2015
15. Co-infection of mice with SARS-CoV-2 and Mycobacterium tuberculosis limits early viral replication but does not affect mycobacterial loads.
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Baker, Paul J., Amaral, Eduardo P., Castro, Ehydel, Bohrer, Andrea C., Torres-Juárez, Flor, Jordan, Cassandra M., Nelson, Christine E., Barber, Daniel L., Johnson, Reed F., Hilligan, Kerry L., and Mayer-Barber, Katrin D.
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MYCOBACTERIUM tuberculosis ,VIRAL replication ,VIRUS diseases ,SARS-CoV-2 ,COVID-19 pandemic - Abstract
Viral co-infections have been implicated in worsening tuberculosis (TB) and during the COVID-19 pandemic, the global rate of TB-related deaths has increased for the first time in over a decade. We and others have previously shown that a resolved prior or concurrent influenza A virus infection in Mycobacterium tuberculosis (Mtb)-infected mice resulted in increased pulmonary bacterial burden, partly through type I interferon (IFN-I)-dependent mechanisms. Here we investigated whether SARS-CoV-2 (SCV2) co-infection could also negatively affect bacterial control of Mtb. Importantly, we found that K18-hACE2 transgenic mice infected with SCV2 one month before, or months after aerosol Mtb exposure did not display exacerbated Mtb infection-associated pathology, weight loss, nor did they have increased pulmonary bacterial loads. However, pre-existing Mtb infection at the time of exposure to the ancestral SCV2 strain in infected K18-hACE2 transgenic mice or the beta variant (B.1.351) in WT C57Bl/6 mice significantly limited early SCV2 replication in the lung. Mtb-driven protection against SCV2 increased with higher bacterial doses and did not require IFN-I, TLR2 or TLR9 signaling. These data suggest that SCV2 co-infection does not exacerbate Mtb infection in mice, but rather the inflammatory response generated by Mtb infection in the lungs at the time of SCV2 exposure restricts viral replication. [ABSTRACT FROM AUTHOR]
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- 2023
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16. IL-10 suppresses T cell expansion while promoting tissue-resident memory cell formation during SARS-CoV-2 infection in rhesus macaques
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Nelson, Christine E., Foreman, Taylor W., Kauffman, Keith D., Sakai, Shunsuke, Gould, Sydnee T., Fleegle, Joel D., Gomez, Felipe, Le Nouën, Cyril, Liu, Xueqiao, Burdette, Tracey L., Garza, Nicole L., Lafont, Bernard A. P., Brooks, Kelsie, Arlehamn, Cecilia S. Lindestam, Weiskopf, Daniela, Sette, Alessandro, Hickman, Heather D., Buchholz, Ursula J., Johnson, Reed F., Brenchley, Jason M., Via, Laura E., and Barber, Daniel L.
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Article - Abstract
The pro- and anti-inflammatory pathways that determine the balance of inflammation and viral control during SARS-CoV-2 infection are not well understood. Here we examine the roles of IFNγ and IL-10 in regulating inflammation, immune cell responses and viral replication during SARS-CoV-2 infection of rhesus macaques. IFNγ blockade tended to decrease lung inflammation based on 18FDG-PET/CT imaging but had no major impact on innate lymphocytes, neutralizing antibodies, or antigen-specific T cells. In contrast, IL-10 blockade transiently increased lung inflammation and enhanced accumulation of virus-specific T cells in the lower airways. However, IL-10 blockade also inhibited the differentiation of virus-specific T cells into airway CD69+CD103+ TRM cells. While virus-specific T cells were undetectable in the nasal mucosa of all groups, IL-10 blockade similarly reduced the frequency of total TRM cells in the nasal mucosa. Neither cytokine blockade substantially affected viral load and infection ultimately resolved. Thus, in the macaque model of mild COVID-19, the pro- and anti-inflammatory effects of IFNγ and IL-10 have no major role in control of viral replication. However, IL-10 has a key role in suppressing the accumulation of SARS-CoV-2-specific T cells in the lower airways, while also promoting TRM at respiratory mucosal surfaces.
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- 2022
17. Antigen-specific CD4 T-cell help rescues exhausted CD8 T cells during chronic viral infection
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Aubert, Rachael D., Kamphorst, Alice O., Sarkar, Surojit, Vezys, Vaiva, Ha, Sang-Jun, Barber, Daniel L., Ye, Lilin, Sharpe, Arlene H., Freeman, gordon J., and Ahmed, Rafi
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- 2011
18. Estimation of the Rate of Killing by Cytotoxic T Lymphocytes in vivo
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Regoes, Roland R., Barber, Daniel L., Ahmed, Rafi, and Antia, Rustom
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- 2007
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19. Host-directed therapy of tuberculosis based on interleukin-1 and type I interferon crosstalk
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Mayer-Barber, Katrin D., Andrade, Bruno B., Oland, Sandra D., Amaral, Eduardo P., Barber, Daniel L., Gonzales, Jacqueline, Derrick, Steven C., Shi, Ruiru, Kumar, Nathella Pavan, Wei, Wang, Yuan, Xing, Zhang, Guolong, Cai, Ying, Babu, Subash, Catalfamo, Marta, Salazar, Andres M., Via, Laura E., Barry, III, Clifton E., and Sher, Alan
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Interferon -- Dosage and administration -- Research ,Tuberculosis -- Research -- Prevention -- Risk factors -- Drug therapy -- Patient outcomes ,Biological response modifiers -- Research ,Interleukins -- Research ,Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
Tuberculosis remains second only to HIV/AIDS as the leading cause of mortality worldwide due to a single infectious agent (1). Despite chemotherapy, the global tuberculosis epidemic has intensified because of [...]
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- 2014
20. Intravascular staining for discrimination of vascular and tissue leukocytes
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Anderson, Kristin G, Mayer-Barber, Katrin, Sung, Heungsup, Beura, Lalit, James, Britnie R, Taylor, Justin J, Qunaj, Lindor, Griffith, Thomas S, Vezys, Vaiva, Barber, Daniel L, and Masopust, David
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- 2014
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21. Phenotypic Profile of Mycobacterium tuberculosis-Specific CD4 T-Cell Responses in People With Advanced Human Immunodeficiency Virus Who Develop Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome.
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Moseki, Raymond M, Barber, Daniel L, Bruyn, Elsa Du, Shey, Muki, Plas, Helen Van der, Wilkinson, Robert J, Meintjes, Graeme, and Riou, Catherine
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IMMUNE reconstitution inflammatory syndrome , *HIV , *CD4 antigen , *T cells , *MYCOBACTERIUM , *MYCOBACTERIUM avium - Abstract
Background Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is a frequent complication of cotreatment for TB and human immunodeficiency virus (HIV)-1. We characterized Mycobacterium tuberculosis (Mtb)-specific CD4 T-cell phenotype and transcription factor profile associated with the development of TB-IRIS. Methods We examined the role of CD4 T-cell transcription factors in a murine model of mycobacterial IRIS. In humans, we used a longitudinal study design to compare the magnitude of antiretroviral therapy, activation, transcription factor profile, and cytotoxic potential of Mtb-specific CD4 T cells between TB-IRIS (n = 25) and appropriate non-IRIS control patients (n = 18) using flow cytometry. Results In the murine model, CD4 T-cell expression of Eomesodermin (Eomes), but not Tbet, was associated with experimentally induced IRIS. In patients, TB-IRIS onset was associated with the expansion of Mtb-specific IFNγ+CD4 T cells (P =.039). Patients with TB-IRIS had higher HLA-DR expression (P =.016), but no differences in the expression of T-bet or Eomes were observed. At TB-IRIS onset, Eomes+Tbet+Mtb-specific IFNγ+CD4+ T cells showed higher expression of granzyme B in patients with TB-IRIS (P =.026). Conclusions Although the murine model of Mycobacterium avium complex-IRIS suggests that Eomes+CD4 T cells underly IRIS, TB-IRIS was not associated with Eomes expression in patients. Mycobacterium tuberculosis -specific IFNγ+CD4 T-cell responses in TB-IRIS patients are differentiated, highly activated, and potentially cytotoxic. [ABSTRACT FROM AUTHOR]
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- 2023
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22. Comparison of the frequency and phenotypic profile of Mycobacterium tuberculosisspecific CD4 T cells between the site of disease and blood in pericardial tuberculosis.
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Du Bruyn, Elsa, Ruzive, Sheena, Howlett, Patrick, Jacobs, Ashley J., Arlehamn, Cecilia S. Lindestam, Sette, Alessandro, Sher, Alan, Mayer-Barber, Katrin D., Barber, Daniel L., Mayosi, Bongani, Ntsekhe, Mpiko, Wilkinson, Robert J., and Riou, Catherine
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T cells ,BLOOD diseases ,CD4 antigen ,PERICARDIUM diseases ,MYCOBACTERIUM ,MYCOBACTERIUM avium paratuberculosis - Abstract
Studies of the immune response at the site of disease in extra-pulmonary tuberculosis (EPTB) disease are scarce. In this study, we compared the cellular profile of Mycobacterium tuberculosis (Mtb)-specific T cells in pericardial fluid and peripheral blood in patients with pericardial TB (PCTB). Whole blood and pericardial fluid (PCF) samples were collected at the time of diagnostic sampling, with repeat blood sampling after completion of anti-tubercular treatment (ATT) in 16 PCTB patients, most of them being HIV-1 infected (n=14). These samples were stimulated ex vivo and the phenotypic and functional cellular profile of PCF and blood was assessed by flow cytometry. We found that lymphocytes were the predominant cell type in PCF in PCTB, with a preferential influx of CD4 T cells. The frequencies of TNF-a producing Mtb-specific granulocytes and Mtb-specific CD4 T cells were significantly higher in PCF compared to blood. Mtb-specific CD4 T cells in PCF exhibited a distinct phenotype compared to those in blood, with greater GrB expression and lower CD27 and KLRG1 expression. We observed no difference in the production IFNg, TNF or IL-2 by Mtb-specific CD4 T cells between the two compartments, but MIP-1b production was lower in the PCF T cells. Bacterial loads were not associated with alterations in the phenotype or function of Mtbspecific CD4 T cells. Upon ATT completion, HLA-DR, Ki-67 and GrB expression was significantly decreased, and relative IL-2 production was increased in peripheral Mtb-specific CD4 T cells. Overall, using an ex vivo assay to compare the immune response towards Mtb in PCF and in blood, we identified significant difference in the phenotypic profile of Mtb-specific CD4 T response between these two compartments. Moreover, we show that the activation profile of peripheral Mtb-specific CD4 T cells could be used to monitor treatment response in PCTB. [ABSTRACT FROM AUTHOR]
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- 2022
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23. Elevated frequencies of highly activated CD4+ T cells in HIV+ patients developing immune reconstitution inflammatory syndrome
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Antonelli, Lis R.V., Mahnke, Yolanda, Hodge, Jessica N., Porter, Brian O., Barber, Daniel L., DerSimonian, Rebecca, Greenwald, Jamieson H., Roby, Gregg, Mican, JoAnn, Sher, Alan, Roederer, Mario, and Sereti, Irini
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- 2010
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24. Th1-driven immune reconstitution disease in Mycobacterium avium–infected mice
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Barber, Daniel L., Mayer-Barber, Katrin D., Antonelli, Lis R.V., Wilson, Mark S., White, Sandra, Caspar, Patricia, Hieny, Sara, Sereti, Irini, and Sher, Alan
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- 2010
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25. T CELL VACCINES: Vaccine-elicited CD4 T cells induce immunopathology after chronic LCMV infection
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Penaloza-MacMaster, Pablo, Barber, Daniel L., Wherry, John E., Provine, Nicholas M., Teigler, Jeffrey E., Parenteau, Lily, Blackmore, Stephen, Borducchi, Erica N., Larocca, Rafael A., Yates, Kathleen B., Shen, Hao, Haining, Nicholas W., Sommerstein, Rami, Pinschewer, Daniel D., Ahmed, Rafi, and Barouch, Dan H.
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- 2015
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26. Visualizing antigen-specific and infected cells in situ predicts outcomes in early viral infection
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Li, Qingsheng, Skinner, Pamela J., Ha, Sang-Jun, Duan, Lijie, Mattila, Teresa L., Hage, Aaron, White, Cara, Barber, Daniel L., O'Mara, Leigh, Southern, Peter J., Reilly, Cavan S., Carlis, John V., Miller, Christopher J., Ahmed, Rafi, and Haase, Ashley T.
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Virus diseases -- Patient outcomes ,Immune response -- Research ,Science and technology - Abstract
In the early stages of viral infection, outcomes depend on a race between expansion of infection and the immune response generated to contain it. We combined in situ tetramer staining with in situ hybridization to visualize, map, and quantify relationships between immune effector cells and their targets in tissues. In simian immunodeficiency virus infections in macaques and lymphocytic choriomeningitis virus infections in mice, the magnitude and timing of the establishment of an excess of effector ceils versus targets were found to correlate with the extent of control and the infection outcome (i.e., control and clearance versus partial or poor control and persistent infection). This method highlights the importance of the location, timing, and magnitude of the immune response needed for a vaccine to be effective against agents of persistent infection, such as HIV-1.
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- 2009
27. Innate and Adaptive Interferons Suppress IL-1α and IL-1β Production by Distinct Pulmonary Myeloid Subsets during Mycobacterium tuberculosis Infection
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Mayer-Barber, Katrin D., Andrade, Bruno B., Barber, Daniel L., Hieny, Sara, Feng, Carl G., Caspar, Patricia, Oland, Sandy, Gordon, Siamon, and Sher, Alan
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- 2011
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28. Molecular Signature of CD8+ T Cell Exhaustion during Chronic Viral Infection
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Wherry, John E., Ha, Sang-Jun, Kaech, Susan M., Haining, Nicholas W., Sarkar, Surojit, Kalia, Vandana, Subramaniam, Shruti, Blattman, Joseph N., Barber, Daniel L., and Ahmed, Rafi
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- 2007
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29. Restoring function in exhausted CD8 T cells during chronic viral infection
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Barber, Daniel L., Wherry, E. John, Masopust, David, Zhu, Baogong, Allison, James P., Sharpe, Arlene H., Freeman, Gordon J., and Ahmed, Rafi
- Published
- 2006
30. Safety and Immunogenicity of a 4-Component Toxoid-Based Staphylococcus aureus Vaccine in Rhesus Macaques.
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Venkatasubramaniam, Arundhathi, Liao, Grant, Cho, Eunice, Adhikari, Rajan P., Kort, Tom, Holtsberg, Frederick W., Elsass, Karen E., Kobs, Dean J., Rudge, Thomas L., Kauffman, Keith D., Lora, Nickiana E., Barber, Daniel L., Aman, M. Javad, and Karauzum, Hatice
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RHESUS monkeys ,STAPHYLOCOCCUS aureus ,EXOTOXIN ,HUMORAL immunity ,VACCINES ,T cells ,ACTINOBACILLUS actinomycetemcomitans - Abstract
Staphylococcus aureus is a leading cause of significant morbidity and mortality and an enormous economic burden to public health worldwide. Infections caused by methicillin-resistant S. aureus (MRSA) pose a major threat as MRSA strains are becoming increasingly prevalent and multi-drug resistant. To this date, vaccines targeting surface-bound antigens demonstrated promising results in preclinical testing but have failed in clinical trials. S. aureus pathogenesis is in large part driven by immune destructive and immune modulating toxins and thus represent promising vaccine targets. Hence, the objective of this study was to evaluate the safety and immunogenicity of a staphylococcal 4-component vaccine targeting secreted bi-component pore-forming toxins (BCPFTs) and superantigens (SAgs) in non-human primates (NHPs). The 4-component vaccine proved to be safe, even when repeated vaccinations were given at a dose that is 5 to 10- fold higher than the proposed human dose. Vaccinated rhesus macaques did not exhibit clinical signs, weight loss, or changes in hematology or serum chemistry parameters related to the administration of the vaccine. No acute, vaccine-related elevation of serum cytokine levels was observed after vaccine administration, confirming the toxoid components lacked superantigenicity. Immunized animals demonstrated high level of toxin-specific total and neutralizing antibodies toward target antigens of the 4-component vaccine as well as cross-neutralizing activity toward staphylococcal BCPFTs and SAgs that are not direct targets of the vaccine. Cross-neutralization was also observed toward the heterologous streptococcal pyogenic exotoxin B. Ex vivo stimulation of PBMCs with individual vaccine components demonstrated an overall increase in several T cell cytokines measured in supernatants. Immunophenotyping of CD4 T cells ex vivo showed an increase in Ag-specific polyfunctional CD4 T cells in response to antigen stimulation. Taken together, we demonstrate that the 4-component vaccine is well-tolerated and immunogenic in NHPs generating both humoral and cellular immune responses. Targeting secreted toxin antigens could be the next-generation vaccine approach for staphylococcal vaccines if also proven to provide efficacy in humans. [ABSTRACT FROM AUTHOR]
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- 2021
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31. Disease extent and anti‐tubercular treatment response correlates with Mycobacterium tuberculosis‐specific CD4 T‐cell phenotype regardless of HIV‐1 status.
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Riou, Catherine, Du Bruyn, Elsa, Ruzive, Sheena, Goliath, Rene T, Lindestam Arlehamn, Cecilia S, Sette, Alessandro, Sher, Alan, Barber, Daniel L, and Wilkinson, Robert J
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TUBERCULOSIS ,MYCOBACTERIUM ,MYCOBACTERIUM tuberculosis ,SPINAL tuberculosis ,PRINCIPAL components analysis ,T cells - Abstract
Objectives: The development of non‐sputum‐based assays for tuberculosis (TB) diagnosis and treatment monitoring is a key priority. Recent data indicate that whole blood‐based assays to assess the phenotype of Mycobacterium tuberculosis (Mtb)‐specific CD4 T cells hold promise for this purpose and require further investigation in well‐characterised TB cohorts. In this study, we investigated the relationship between the phenotypic signature of Mtb‐specific CD4 responses, TB disease extent and treatment response. Methods: Using flow cytometry, we measured the expression of phenotypic and functional markers (HLA‐DR, CD27, CD153, KLRG1, IL‐2, MIP‐1β, TNF‐α and IFN‐γ) on Mtb‐specific CD4 T‐cells in whole blood from 161 participants of varying TB and HIV status. TB disease extent was graded as a continuum using the Xpertct value, C‐reactive protein, Timika radiographic score and monocyte/lymphocyte ratio. Results: The phenotypic profile of Mtb‐specific CD4 T cells pre‐anti‐tubercular treatment (ATT) strongly correlated with disease extent, irrespective of HIV status. ATT associated with major changes in the phenotype of Mtb‐specific CD4 T cells, with decreased expression of HLA‐DR and increased CD27 and CD153 expression. Principal component analysis showed an almost complete separation between latent TB infection (LTBI) and active TB (aTB) pre‐ATT groups, whereas the profile of the aTB post‐ATT group overlapped with the LTBI group. However, in patients experiencing treatment failure or relapse, no significant changes were observed in Mtb‐specific CD4 T‐cell phenotype pre‐ and post‐ATT. Conclusion: Whole blood‐based assays of Mtb‐specific CD4 T‐cell activation and maturation markers can be used as non‐sputum‐based biomarkers of disease extent and treatment monitoring in TB, regardless of HIV‐1 status. [ABSTRACT FROM AUTHOR]
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- 2020
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32. Vaccine-Elicited CD4 T Cells Induce Immunopathology Following Chronic LCMV Infection
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Penaloza-MacMaster, Pablo, Barber, Daniel L., Wherry, E. John, Provine, Nicholas M., Teigler, Jeffrey E., Parenteau, Lily, Blackmore, Stephen, Borducchi, Erica N., Larocca, Rafael A., Yates, Kathleen B., Shen, Hao, Haining, W. Nicholas, Sommerstein, Rami, Pinschewer, Daniel D., Ahmed, Rafi, and Barouch, Dan. H.
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CD4-Positive T-Lymphocytes ,Inflammation ,Multiple Organ Failure ,Vaccination ,Epitopes, T-Lymphocyte ,Viral Vaccines ,Adaptive Immunity ,CD8-Positive T-Lymphocytes ,Viral Load ,Antibodies, Viral ,Virus Replication ,Article ,Mice, Inbred C57BL ,Immune System Diseases ,Animals ,Arenaviridae Infections ,Cytokines ,Lymphocytic choriomeningitis virus ,Antigens, Viral ,Immunologic Memory - Abstract
CD4 T cells promote innate and adaptive immune responses, but how vaccine-elicited CD4 T cells contribute to immune protection remains unclear. Here we evaluated whether induction of virus-specific CD4 T cells by vaccination would protect mice against infection with chronic lymphocytic choriomeningitis virus (LCMV). Immunization with vaccines that selectively induced CD4 T cell responses resulted in catastrophic inflammation and mortality following challenge with a persistent strain of LCMV. Immunopathology required antigen-specific CD4 T cells and was associated with a cytokine storm, generalized inflammation, and multi-organ system failure. Virus-specific CD8 T cells or antibodies abrogated the pathology. These data demonstrate that vaccine-elicited CD4 T cells in the absence of effective antiviral immune responses can trigger lethal immunopathology.
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- 2015
33. Advancing Translational Science for Pulmonary Nontuberculous Mycobacterial Infections. A Road Map for Research.
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Daniel-Wayman, Shelby, Abate, Getahun, Barber, Daniel L, Bermudez, Luiz E, Coler, Rhea N, Cynamon, Michael H, Daley, Charles L, Davidson, Rebecca M, Dick, Thomas, Floto, R Andres, Henkle, Emily, Holland, Steven M, Jackson, Mary, Lee, Richard E, Nuermberger, Eric L, Olivier, Kenneth N, Ordway, Diane J, Prevots, D Rebecca, Sacchettini, James C, and Salfinger, Max
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- 2019
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34. Control of Mycobacterium tuberculosis infection by a subset of lung parenchyma homing CD4 T cells
- Author
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Sakai, Shunsuke, Kauffman, Keith D., Schenkel, Jason M., McBerry, Cortez C., Mayer-Barber, Katrin D., Masopust, David, and Barber, Daniel L.
- Subjects
CD4-Positive T-Lymphocytes ,Mice, Knockout ,Receptors, CXCR3 ,CX3C Chemokine Receptor 1 ,Mycobacterium tuberculosis ,Th1 Cells ,Flow Cytometry ,Adoptive Transfer ,Article ,Mice, Inbred C57BL ,Interferon-gamma ,Mice ,Mice, Congenic ,Microscopy, Fluorescence ,Cell Movement ,Host-Pathogen Interactions ,Animals ,Blood Vessels ,Leukocyte Common Antigens ,Tuberculosis ,Lectins, C-Type ,Receptors, Chemokine ,Receptors, Immunologic ,Lung - Abstract
Th1 cells are critical for containment of Mycobacterium tuberculosis infection, but little else is known about the properties of protective CD4 T cell responses. In this study, we show that the pulmonary Th1 response against M. tuberculosis is composed of two populations that are either CXCR3(hi) and localize to lung parenchyma or are CX3CR1(hi)KLRG1(hi) and are retained within lung blood vasculature. M. tuberculosis-specific parenchymal CD4 T cells migrate rapidly back into the lung parenchyma upon adoptive transfer, whereas the intravascular effectors produce the highest levels of IFN-γ in vivo. Importantly, parenchymal T cells displayed greater control of infection compared with the intravascular counterparts upon transfer into susceptible T cell-deficient hosts. Thus, we identified a subset of naturally generated M. tuberculosis-specific CD4 T cells with enhanced protective capacity and showed that control of M. tuberculosis correlates with the ability of CD4 T cells to efficiently enter the lung parenchyma rather than produce high levels of IFN-γ.
- Published
- 2014
35. Killing of targets by effector CD8$^+$T cells in the mouse spleen follows the law of mass action
- Author
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Ganusov, Vitaly V., Barber, Daniel L., and De Boer, Rob J.
- Subjects
FOS: Biological sciences ,Populations and Evolution (q-bio.PE) ,Quantitative Biology - Populations and Evolution ,Quantitative Biology - Quantitative Methods ,Quantitative Methods (q-bio.QM) - Abstract
It has been difficult to measure efficacy of T cell-based vaccines and to correlate efficacy of CD8$^+$T cell responses with protection against viral infections. In part, this difficulty is due to our poor understanding of the in vivo efficacy of CD8$^+$T cells. Using a recently developed experimental method of in vivo cytotoxicity we investigated quantitative aspects of killing of peptide-pulsed targets by effector and memory CD8$^+$T cells, specific to three epitopes of lymphocytic choriomeningitis virus (LCMV), in the mouse spleen. By analyzing data on killing of targets with varying number of epitope-specific effector and memory CD8$^+$T cells, we find that killing of targets by effectors follows the law of mass-action, that is the death rate of peptide-pulsed targets is proportional to the frequency of CTLs in the spleen. In contrast, killing of targets by memory CD8$^+$T cells does not follow the mass action law because the death rate of targets saturates at high frequencies of memory CD8$^+$T cells. For both effector and memory cells, we also find no support for a killing term that includes the decrease of the death rate of targets with increasing target cell density. Importantly, we find that at low CD8$^+$T cell frequencies, effector and memory CD8$^+$T cells on the per capita basis are equally efficient at killing peptide-pulsed targets. Our framework provides the guideline for the calculation of the level of memory CD8$^+$T cells required to provide sterilizing protection against viral infection. Our results thus form a basis for quantitative understanding of the process of killing of virus-infected cells by T cell responses in tissues and can be used to correlate the phenotype of vaccine-induced memory CD8 T cells with their killing efficacy in vivo.
- Published
- 2009
36. Revisiting estimates of CTL killing rates in vivo
- Author
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Rodrigues, Mauricio, Yates, Andrew, Graw, Frederik, Barber, Daniel L., Ahmed, Rafi, Regoes, Roland R., and Antia, Rustom
- Subjects
hemic and immune systems ,chemical and pharmacologic phenomena - Abstract
Recent experimental advances have allowed the estimation of the in vivo rates of killing of infected target cells by cytotoxic T lymphocytes (CTL). We present several refinements to a method applied previously to quantify killing of targets in the spleen using a dynamical model. We reanalyse data previously used to estimate killing rates of CTL specific for two epitopes of lymphocytic choriomeningitis virus (LCMV) in mice and show that, contrary to previous estimates the “killing rate” of effector CTL is approximately twice that of memory CTL. Further, our method allows the fits to be visualized, and reveals one potentially interesting discrepancy between fits and data. We discuss extensions to the basic CTL killing model to explain this discrepancy and propose experimental tests to distinguish between them.
- Published
- 2007
37. Th1 Differentiation Drives the Accumulation of Intravascular, Non-protective CD4 T Cells during Tuberculosis.
- Author
-
Sallin, Michelle A., Sakai, Shunsuke, Kauffman, Keith D., Young, Howard A., Jinfang Zhu, and Barber, Daniel L.
- Abstract
Recent data indicate that the differentiation state of Th1 cells determines their protective capacity against tuberculosis. Therefore, we examined the role of Th1-polarizing factors in the generation of protective and non-protective subsets of Mtb-specific Th1 cells. We find that IL-12/23p40 promotes Th1 cell expansion and maturation beyond the CD73
+ CXCR3+ T-betdim stage, and T-bet prevents deviation of Th1 cells into Th17 cells. Nevertheless, IL- 12/23p40 and T-bet are also essential for the production of a prominent subset of intravascular CX3CR1+ KLRG1+ Th1 cells that persists poorly and can neither migrate into the lung parenchyma nor control Mtb growth. Furthermore, T-bet suppresses development of CD69+ CD103+ tissue resident phenotype effectors in lung. In contrast, Th1-cell-derived IFN-γ inhibits the accumulation of intravascular CX3CR1+ KLRG1+ Th1 cells. Thus, although IL-12 and T-bet are essential host survival factors, they simultaneously oppose lung CD4 T cell responses at several levels, demonstrating the dual nature of Th1 polarization in tuberculosis. [ABSTRACT FROM AUTHOR]- Published
- 2017
- Full Text
- View/download PDF
38. CD4 T Cell-Derived IFN-γ Plays a Minimal Role in Control of Pulmonary Mycobacterium tuberculosis Infection and Must Be Actively Repressed by PD-1 to Prevent Lethal Disease.
- Author
-
Sakai, Shunsuke, Kauffman, Keith D., Sallin, Michelle A., Sharpe, Arlene H., Young, Howard A., Ganusov, Vitaly V., and Barber, Daniel L.
- Subjects
CD4 antigen ,MYCOBACTERIUM tuberculosis ,T cells ,PROGRAMMED cell death 1 receptors ,INTERFERONS - Abstract
IFN-γ–producing CD4 T cells are required for protection against Mycobacterium tuberculosis (Mtb) infection, but the extent to which IFN-γ contributes to overall CD4 T cell-mediated protection remains unclear. Furthermore, it is not known if increasing IFN-γ production by CD4 T cells is desirable in Mtb infection. Here we show that IFN-γ accounts for only ~30% of CD4 T cell-dependent cumulative bacterial control in the lungs over the first six weeks of infection, but >80% of control in the spleen. Moreover, increasing the IFN-γ–producing capacity of CD4 T cells by ~2 fold exacerbates lung infection and leads to the early death of the host, despite enhancing control in the spleen. In addition, we show that the inhibitory receptor PD-1 facilitates host resistance to Mtb by preventing the detrimental over-production of IFN-γ by CD4 T cells. Specifically, PD-1 suppressed the parenchymal accumulation of and pathogenic IFN-γ production by the CXCR3
+ KLRG1- CX3CR1- subset of lung-homing CD4 T cells that otherwise mediates control of Mtb infection. Therefore, the primary role for T cell-derived IFN-γ in Mtb infection is at extra-pulmonary sites, and the host-protective subset of CD4 T cells requires negative regulation of IFN-γ production by PD-1 to prevent lethal immune-mediated pathology. [ABSTRACT FROM AUTHOR]- Published
- 2016
- Full Text
- View/download PDF
39. Type I IFN Induction via Poly-ICLC Protects Mice against Cryptococcosis.
- Author
-
Sionov, Edward, Mayer-Barber, Katrin D., Chang, Yun C., Kauffman, Keith D., Eckhaus, Michael A., Salazar, Andres M., Barber, Daniel L., and Kwon-Chung, Kyung J.
- Subjects
TYPE I interferons ,CRYPTOCOCCUS neoformans ,IMMUNE response ,CELLULAR immunity ,LABORATORY mice - Abstract
Cryptococcus neoformans is the most common cause of fungal meningoencephalitis in AIDS patients. Depletion of CD4 cells, such as occurs during advanced AIDS, is known to be a critical risk factor for developing cryptococcosis. However, the role of HIV-induced innate inflammation in susceptibility to cryptococcosis has not been evaluated. Thus, we sought to determine the role of Type I IFN induction in host defense against cryptococci by treatment of C. neoformans (H99) infected mice with poly-ICLC (pICLC), a dsRNA virus mimic. Unexpectedly, pICLC treatment greatly extended survival of infected mice and reduced fungal burdens in the brain. Protection from cryptococcosis by pICLC-induced Type I IFN was mediated by MDA5 rather than TLR3. PICLC treatment induced a large, rapid and sustained influx of neutrophils and Ly6C
high monocytes into the lung while suppressing the development of eosinophilia. The pICLC-mediated protection against H99 was CD4 T cell dependent and analysis of CD4 T cell polyfunctionality showed a reduction in IL-5 producing CD4 T cells, marginal increases in Th1 cells and dramatic increases in RORγt+ Th17 cells in pICLC treated mice. Moreover, the protective effect of pICLC against H99 was diminished in IFNγ KO mice and by IL-17A neutralization with blocking mAbs. Furthermore, pICLC treatment also significantly extended survival of C. gattii infected mice with reduced fungal loads in the lungs. These data demonstrate that induction of type I IFN dramatically improves host resistance against the etiologic agents of cryptococcosis by beneficial alterations in both innate and adaptive immune responses. [ABSTRACT FROM AUTHOR]- Published
- 2015
- Full Text
- View/download PDF
40. Vaccine-elicited CD4 T cells induce immunopathology after chronic LCMV infection.
- Author
-
Penaloza-MacMaster, Pablo, Barber, Daniel L., Wherry, E. John, Provine, Nicholas M., Teigler, Jeffrey E., Parenteau, Lily, Blackmore, Stephen, Borducchi, Erica N., Larocca, Rafael A., Yates, Kathleen B., Hao Shen, Haining, W. Nicholas, Sommerstein, Rami, Pinschewer, Daniel D., Ahmed, Rafi, and Barouch, Dan H.
- Subjects
- *
IMMUNOLOGY , *LYMPHOCYTIC choriomeningitis , *EFFECT of drugs on T cells , *CD4 antigen , *NATURAL immunity , *IMMUNOPATHOLOGY , *IMMUNE response , *IMMUNOLOGY of inflammation , *VACCINATION - Abstract
CD4 T cells promote innate and adaptive immune responses, but how vaccine-elicited CD4 T cells contribute to immune protection remains unclear. We evaluated whether induction of virus-specific CD4 T cells by vaccination would protect mice against infection with chronic lymphocytic choriomeningitis virus (LCMV). Immunization with vaccines that selectively induced CD4 T cell responses resulted in catastrophic inflammation and mortality after challenge with a persistent strain of LCMV. Immunopathology required antigen-specific CD4 T cells and was associated with a cytokine storm, generalized inflammation, and multi-organ system failure. Virus-specific CD8 T cells or antibodies abrogated the pathology. These data demonstrate that vaccine-elicited CD4 T cells in the absence of effective antiviral immune responses can trigger lethal immunopathology. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
41. PD-L1 up-regulation restrains Th17 cell differentiation in STAT3 loss- and STAT1 gain-of-function patients
- Author
-
Zhang, Yuan, Ma, Chi A., Lawrence, Monica G., Break, Timothy J., O’Connell, Michael P., Lyons, Jonathan J., López, Diego B., Barber, John S., Zhao, Yongge, Barber, Daniel L., Freeman, Alexandra F., Holland, Steven M., Lionakis, Michail S., and Milner, Joshua D.
- Subjects
Brief Definitive Report - Abstract
Patients with hypomorphic mutations in STAT3 and patients with hypermorphic mutations in STAT1 share several clinical and cellular phenotypes suggesting overlapping pathophysiologic mechanisms. We, therefore, examined cytokine signaling and CD4+ T cell differentiation in these cohorts to characterize common pathways. As expected, differentiation of Th17 cells was impaired in both cohorts. We found that STAT1 was hyperphosphorylated in response to cytokine stimulation in both cohorts and that STAT1-dependent PD-L1 up-regulation—known to inhibit Th17 differentiation in mouse models—was markedly enhanced as well. Overexpression of SOCS3 strongly inhibited phosphorylation of STAT1 and PD-L1 up-regulation, suggesting that diminished SOCS3 expression may lead to the observed effects. Defects in Th17 differentiation could be partially overcome in vitro via PD-L1 inhibition and in a mouse model of STAT3 loss-of-function by crossing them with PD-1 knockout mice. PD-L1 may be a potential therapeutic target in several genetic diseases of immune deficiency affecting cytokine signaling.
- Published
- 2017
- Full Text
- View/download PDF
42. CD4 T cells are rapidly depleted from tuberculosis granulomas following acute SIV co-infection.
- Author
-
Foreman, Taylor W., Nelson, Christine E., Kauffman, Keith D., Lora, Nickiana E., Vinhaes, Caian L., Dorosky, Danielle E., Sakai, Shunsuke, Gomez, Felipe, Fleegle, Joel D., Parham, Melanie, Perera, Shehan R., Lindestam Arlehamn, Cecilia S., Sette, Alessandro, Brenchley, Jason M., Queiroz, Artur T.L., Andrade, Bruno B., Kabat, Juraj, Via, Laura E., and Barber, Daniel L.
- Abstract
HIV /Mycobacterium tuberculosis (Mtb) co-infected individuals have an increased risk of tuberculosis prior to loss of peripheral CD4 T cells, raising the possibility that HIV co-infection leads to CD4 T cell depletion in lung tissue before it is evident in blood. Here, we use rhesus macaques to study the early effects of simian immunodeficiency virus (SIV) co-infection on pulmonary granulomas. Two weeks after SIV inoculation of Mtb-infected macaques, Mtb-specific CD4 T cells are dramatically depleted from granulomas, before CD4 T cell loss in blood, airways, and lymph nodes, or increases in bacterial loads or radiographic evidence of disease. Spatially, CD4 T cells are preferentially depleted from the granuloma core and cuff relative to B cell-rich regions. Moreover, live imaging of granuloma explants show that intralesional CD4 T cell motility is reduced after SIV co-infection. Thus, granuloma CD4 T cells may be decimated before many co-infected individuals experience the first symptoms of acute HIV infection. [Display omitted] • SIV rapidly replicates in Mtb granulomas of co-infected macaques • Granuloma CD4 T cells are depleted before those in blood, BAL, LNs, or spleen • CCR5
+ Eomes− Mtb-specific Th1 and Th1∗ cells in granulomas are preferentially depleted • SIV co-infection reduces motility of CD4 T cells in granulomas HIV-mediated destruction of CD4 T cells enhances susceptibility to Mycobacterium tuberculosis. Using macaques, Foreman et al. show that CD4 T cells in granulomas are depleted very rapidly after SIV co-infection, indicating that loss of immunity at the site of bacterial replication occurs long before signs of peripheral T cell depletion. [ABSTRACT FROM AUTHOR]- Published
- 2022
- Full Text
- View/download PDF
43. Mycobacterial Antigen Driven Activation of CD14++CD16− Monocytes Is a Predictor of Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome.
- Author
-
Andrade, Bruno B., Singh, Amrit, Narendran, Gopalan, Schechter, Melissa E., Nayak, Kaustuv, Subramanian, Sudha, Anbalagan, Selvaraj, Jensen, Stig M. R., Porter, Brian O., Antonelli, Lis R., Wilkinson, Katalin A., Wilkinson, Robert J., Meintjes, Graeme, van der Plas, Helen, Follmann, Dean, Barber, Daniel L., Swaminathan, Soumya, Sher, Alan, and Sereti, Irini
- Subjects
IMMUNE reconstitution inflammatory syndrome ,ANTIGENS ,TUBERCULOSIS treatment ,ANTIRETROVIRAL agents ,CD antigens ,MONOCYTES ,THERAPEUTICS - Abstract
Paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is an aberrant inflammatory response occurring in a subset of TB-HIV co-infected patients initiating anti-retroviral therapy (ART). Here, we examined monocyte activation by prospectively quantitating pro-inflammatory plasma markers and monocyte subsets in TB-HIV co-infected patients from a South Indian cohort at baseline and following ART initiation at the time of IRIS, or at equivalent time points in non-IRIS controls. Pro-inflammatory biomarkers of innate and myeloid cell activation were increased in plasma of IRIS patients pre-ART and at the time of IRIS; this association was confirmed in a second cohort in South Africa. Increased expression of these markers correlated with elevated antigen load as measured by higher sputum culture grade and shorter duration of anti-TB therapy. Phenotypic analysis revealed the frequency of CD14
++ CD16− monocytes was an independent predictor of TB-IRIS, and was closely associated with plasma levels of CRP, TNF, IL-6 and tissue factor during IRIS. In addition, production of inflammatory cytokines by monocytes was higher in IRIS patients compared to controls pre-ART. These data point to a major role of mycobacterial antigen load and myeloid cell hyperactivation in the pathogenesis of TB-IRIS, and implicate monocytes and monocyte-derived cytokines as potential targets for TB-IRIS prevention or treatment. [ABSTRACT FROM AUTHOR]- Published
- 2014
- Full Text
- View/download PDF
44. Role of IL-6 in Mycobacterium avium-Associated Immune Reconstitution Inflammatory Syndrome.
- Author
-
Barber, Daniel L., Andrade, Bruno B., McBerry, Cortez, Sereti, Irini, and Sher, Alan
- Subjects
- *
IMMUNE reconstitution inflammatory syndrome , *ANTIRETROVIRAL agents , *HIV infections , *THERAPEUTICS , *HIV-positive persons , *T cells - Abstract
Immune reconstitution inflammatory syndrome (IRIS) is a major adverse event of antiretroviral therapy in HIV infection, and paradoxically occurs as HIV viremia is suppressed and CD4 T cell numbers recover. IRIS reflects pathogenic immune responses against opportunistic infections acquired during the period of immunodeficiency, but little is understood about the mechanisms of inflammatory pathology. In this study, we show that IL-6 and C-reactive protein levels transiently rise at the time of the IRIS event in HIV-infected patients, umasking Mycobacterium avium complex infection after starting antiretroviral therapy. To directly test the role of IL-6 in IRIS pathology, we used a model of experimentally inducible IRIS in which M. avium-infected T cell-deficient mice undergo a fatal inflammatory disease after reconstitution with CD4 T cells. We find that IL-6 neutralization reduces C-reactive protein levels, alleviates wasting disease, and extends host survival during experimental IRIS. Moreover, we show that combined blockade of IL-6 and IFN-γ further reduces IRIS pathology, even after the onset of wasting disease. The combination of these clinical and experimental-model data show that the IL-6 pathway is not only a biomarker of mycobacterial IRIS but also a major mediator of pathology distinct from IFN-γ and may be a useful target for therapeutic intervention. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
45. Cord Factor and Peptidoglycan Recapitulate the Th17-Promoting Adjuvant Activity of Mycobacteria through Mincle/CARD9 Signaling and the Inflammasome.
- Author
-
Shenderov, Kevin, Barber, Daniel L., Mayer-Barber, Katrin D., Gurcha, Sudagar S., Jankovic, Dragana, Feng, Carl G., Oland, Sandy, Hieny, Sara, Caspar, Pat, Sho Yamasaki, Xin Lin, Ting, Jenny P. -Y., Trinchieri, Giorgio, Besra, Gurdyal S., Cerundolo, Vincenzo, and Sher, Alan
- Subjects
- *
T helper cells , *PEPTIDOGLYCANS , *TREHALOSE dimycolate , *MYCOBACTERIA , *CASPASES , *INFLAMMATION , *IMMUNOREGULATION - Abstract
Although adjuvants are critical vaccine components, their modes of action are poorly understood. In this study, we investigated the mechanisms by which the heat-killed mycobacteria in CFA promote Th17 CD4+ T cell responses. We found that IL-17 secretion by CD4+ T cells following CFA immunization requires MyD88 and IL-1β/IL-1R signaling. Through measurement of Ag-specific responses after adoptive transfer of OTII cells, we confirmed that MyD88-dependent signaling controls Th17 differentiation rather than simply production of IL-17. Additional experiments showed that CFA-induced Th17 differentiation involves IL-1β processing by the inflammasome, as mice lacking caspase-1, ASC, or NLRP3 exhibit partially defective responses after immunization. Biochemical fractionation studies further revealed that peptidoglycan is the major component of heat-killed mycobacteria responsible for inflammasome activation. By assaying Il1b transcripts in the injection site skin of CFA-immunized mice, we found that signaling through the adaptor molecule caspase activation and recruitment domain 9 (CARD9) plays a major role in triggering pro-IL-1β expression. Moreover, we demonstrated that recognition of the mycobacterial glycolipid trehalose dimycolate (cord factor) by the C-type lectin receptor mincle partially explains this CARD9 requirement. Importantly, purified peptidoglycan and cord factor administered in mineral oil synergized to recapitulate the Th17-promoting activity of CFA, and, as expected, this response was diminished in caspase-1- and CARD9-deficient mice. Taken together, these findings suggest a general strategy for the rational design of Th17-skewing adjuvants by combining agonists of the CARD9 pathway with inflammasome activators. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
46. Plasma Heme Oxygenase-1 Levels Distinguish Latent or Successfully Treated Human Tuberculosis from Active Disease
- Author
-
Andrade, Bruno B., Pavan Kumar, Nathella, Mayer-Barber, Katrin D., Barber, Daniel L., Sridhar, Rathinam, Rekha, Vaithilingam V. Banu, Jawahar, Mohideen S., Nutman, Thomas B., Sher, Alan, and Babu, Subash
- Subjects
HEME oxygenase ,TUBERCULOSIS treatment ,OXIDATIVE stress ,ANTIOXIDANTS ,CYTOPROTECTION ,MYCOBACTERIAL diseases ,GENE expression - Abstract
Background: Tuberculosis (TB) is associated with oxidative stress and the induction of host anti-oxidants to counteract this response. Heme oxygenase-1 (HO-1) is a critical promoter of cytoprotection in diverse disease models including mycobacterial infection. Nevertheless, the pattern of expression of HO-1 in human tuberculosis has not been studied. Here, we examine expression of HO-1 in M. tuberculosis-exposed and -infected individuals and test its ability to distinguish active from latent and successfully treated TB cases. In addition, we assess correlations between plasma levels of HO-1 and cytokines closely associated with the immunopathogenesis of TB. Methods: Cross-sectional and longitudinal analyses of levels of HO-1, acute phase proteins and pro-inflammatory cytokines were performed in plasma samples from individuals with active pulmonary, extra-pulmonary or latent TB infection and healthy controls as part of a prospective cohort study in South India. Results: Systemic levels of HO-1 were dramatically increased in individuals with active pulmonary and extra-pulmonary tuberculosis and particularly those with bilateral lung lesions and elevated bacillary loads in sputum. HO-1 levels effectively discriminated active from latent tuberculosis with higher predictive values than either C-reactive protein or serum amyloid protein. Moreover, there was a marked reduction in HO-1 levels in active TB cases following anti-tuberculous therapy but not in those who failed treatment. Pulmonary TB patients displaying the highest concentrations of HO-1 in plasma exhibited significantly elevated plasma levels of interleukin (IL)-10, interferon (IFN)-γ and IL-17 and diminished levels of tumor necrosis factor (TNF)-α. Conclusion: These findings establish HO-1 levels as a potentially useful parameter for distinguishing active from latent or treated pulmonary tuberculosis, that is superior in this respect to the measurement of other acute inflammatory proteins. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
47. Immune reconstitution inflammatory syndrome: the trouble with immunity when you had none.
- Author
-
Barber, Daniel L., Andrade, Bruno B., Sereti, Irini, and Sher, Alan
- Subjects
- *
IMMUNE reconstitution inflammatory syndrome , *IMMUNITY , *HIV infections , *HIGHLY active antiretroviral therapy , *IMMUNE system , *T cells , *PHYSIOLOGY - Abstract
Some individuals who are infected with HIV rapidly deteriorate shortly after starting antiretroviral therapy, despite effective viral suppression. This reaction, referred to as immune reconstitution inflammatory syndrome (IRIS), is characterized by tissue-destructive inflammation and arises as CD4+ T cells re-emerge. It has been proposed that IRIS is caused by a dysregulation of the expanding population of CD4+ T cells specific for a co-infecting opportunistic pathogen. Here, we argue that IRIS instead results from hyper-responsiveness of the innate immune system to T cell help, a mechanism that may be shared by the many manifestations of IRIS that occur following the reversal of other types of immunosuppression in pathogen-infected hosts. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
48. CD4 T Cells Promote Rather than Control Tuberculosis in the Absence of PD-1-Mediated Inhibition.
- Author
-
Barber, Daniel L., Mayer-Barber, Katrin D., Feng, Carl G., Sharpe, Arlene H., and Sher, Alan
- Subjects
- *
CD4 antigen , *MYCOBACTERIUM tuberculosis , *T cells , *DISEASE exacerbation , *LABORATORY mice , *DISEASE susceptibility , *CELL receptors , *PREVENTION - Abstract
Although CD4 T cells are required for host resistance to Mycobacterium tuberculosis, they may also contribute to pathology. In this study, we examine the role of the inhibitory receptor PD-1 and its ligand PD-L1 during M. tuberculosis infection. After aerosol exposure, PD-1 knockout (KO) mice develop high numbers of M. tuberculosis-specific CD4 T cells but display markedly increased susceptibility to infection. Importantly, we show that CD4 T cells themselves drive the increased bacterial loads and pathology seen in infected PD-1 KO mice, and PD-1 deficiency in CD4 T cells is sufficient to trigger early mortality. PD-L1 KO mice also display enhanced albeit less severe susceptibility, indicating that T cells are regulated by multiple PD ligands during M. tuberculosis infection. M. tuberculosis-specific CD8 T cell responses were normal in PD-1 KO mice, and CD8 T cells only had a minor contribution to the exacerbated disease in the M. tuberculosis-infected PD-1 KO and PD-L1 KO mice. Thus, in the absence of the PD-1 pathway, M. tuberculosis benefits from CD4 T cell responses, and host resistance requires inhibition by PD-1 to prevent T cell-driven exacerbation of the infection. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
49. Killing of Targets by CD8+ T Cells in the Mouse Spleen Follows the Law of Mass Action.
- Author
-
Ganusov, Vitaly V., Barber, Daniel L., and De Boer, Rob J.
- Subjects
- *
VIRUS diseases , *T cells , *SPLEEN , *LYMPHOCYTIC choriomeningitis virus , *PEPTIDES , *INFECTION , *ARENAVIRUSES , *EPITOPES , *LABORATORY mice - Abstract
It has been difficult to correlate the quality of T cell responses with protection against viral infections. To investigate the relationship between efficacy and magnitude of T cell responses, we quantify the rate at which individual CD8+ effector and memory T cells kill target cells in the mouse spleen. Using mathematical modeling, we analyze recent data on the loss of target cells pulsed with three different peptides from the mouse lymphocytic choriomeningitis virus (LCMV) in mouse spleens with varying numbers of epitope-specific CD8+ T cells. We find that the killing of targets follows the law of massaction, i.e., the death rate of individual target cells remains proportional to the frequency (or the total number) of specific CD8+ T cells in the spleen despite the fact that effector cell densities and effector to target ratios vary about a 1000-fold. The killing rate of LCMV-specific CD8+ T cells is largely independent of T cell specificity and differentiation stage. Our results thus allow one to calculate the critical T cell concentration at which growth of a virus with a given replication rate can be prevented from the start of infection by memory CD8+ T cell response. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
50. Continuous recruitment of naive T cells contributes to heterogeneity of antiviral CD8 T cells during persistent infection.
- Author
-
Vezys, Vaiva, Masopust, David, Kemball, Christopher C., Barber, Daniel L., O'Mara, Leigh A., Larsen, Christian P., Pearson, Thomas C., Ahmed, Raft, and Lukacher, Aron E.
- Subjects
BACTERIA ,CD antigens ,T cells ,PHENOTYPES ,ANTIGENS ,CELL populations - Abstract
Numerous microbes establish persistent infections, accompanied by antigen-specific CD8 T cell activation. Pathogen-specific T cells in chronically infected hosts are often phenotypitally and functionally variable, as well as distinct from T cells responding to nonpersistent infections; this phenotypic heterogeneity has been attributed to an ongoing reencounter with antigen. Paradoxically, maintenance of memory CD8 T cells to acutely resolved infections is antigen independent, whereas there is a dependence on antigen for T cell survival in chronically infected hosts. Using two chronic viral infections, we demonstrate that new naive antigen-specific CD8 T cells are primed after the acute phase of infection. These newly recruited T cells are phenotypically distinct from those primed earlier. Long-lived antiviral CD8 T cells are defective in self-renewal, and lack of thymic output results in the decline of virus-specific CD8 T cells, indicating that newly generated T cells preserve antiviral CD8 T cell populations during chronic infection. These findings reveal a novel role for antigen in maintaining virus-specific CD8 T cells during persistent infection and provide insight toward understanding T cell differentiation in chronic infection. [ABSTRACT FROM AUTHOR]
- Published
- 2006
- Full Text
- View/download PDF
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