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Psoriasis is a skin disease that is inflammatory and persistent, causing a high rate of recurrence, poor quality of life, and significant socioeconomic burden. Its main pathological manifestations are abnormal activation and infiltration of T cells and excessive proliferation of keratinocytes (KCs). The great majority of patients with psoriasis will relapse after remission. It usually lasts a lifetime and necessitates long‐term treatment strategies. During periods of activity and remission, one of the main cell types in psoriasis is memory T cells, which include tissue‐resident memory T (TRM) cells, central memory T (TCM) cells, and effector memory T (TEM) cells. They work by releasing inflammatory factors, cytotoxic particles, or altering cell subpopulations, leading to increased inflammation or recurrence. This review summarizes the role of memory T cells in the pathology and treatment of psoriasis, with a view to potential novel therapies and therapeutic targets. [ABSTRACT FROM AUTHOR]

Background: Ovarian hormones are known to modulate the immune system in the female genital tract (FGT). We sought to define the impact of the menstrual cycle on the mucosal HIV target cell levels, and tissue-resident CD4 T cells. Materials and methods: Here, we characterized the distribution, phenotype, and function of CD4 T cells with special emphasis on HIV target cells (CCR5+ and a4b7+) as well as tissue-resident memory (TRM; CD69+ and CD103+) CD4 T cells in FGT of cycling women. Peripheral blood and Endocervical cells (ECcollected from cytobrush) were collected from 105 healthy women and performed multicolor flow cytometry to characterize the various subsets of CD4 T cells. Cervicovaginal lavage (CVL) were collected for cytokine analysis and plasma were collected for hormonal analysis. All parameters were compared between follicular and luteal phase of menstrual cycle. Results: Our findings revealed no significant difference in the blood CD4 T cell subsets between the follicular and luteal phase. However, in EC, the proportion of several cell types was higher in the follicular phase compared to the luteal phase of menstrual cycle, including CCR5+a4b7-cells (p=0.01), CD69+CD103+ TRM (p=0.02), CCR5+CD69+CD103+ TRM (p=0.001) and FoxP3+ CD4 T cells (p=0.0005). In contrast, a4b7+ CCR5-cells were higher in the luteal phase (p=0.0004) compared to the follicular phase. In addition, we also found that hormonal levels (P4/E2 ratio) and cytokines (IL-5 and IL-6) were correlated with CCR5+ CD4 T cells subsets during the follicular phase of the menstrual cycle. Conclusion: Overall, these findings suggest the difference in the expression of CCR5 and a4b7 in TRM CD4 T cell subsets in endocervix of HIV seronegative women between the follicular and luteal phase. Increase in the CCR5+ expression on TRM subsets could increase susceptibility to HIV infection during follicular phase of the menstrual cycle. [ABSTRACT FROM AUTHOR]

Background: Ovarian hormones are known to modulate the immune system in the female genital tract (FGT). We sought to define the impact of the menstrual cycle on the mucosal HIV target cell levels, and tissue-resident CD4 T cells. Materials and Methods: Here, we characterized the distribution, phenotype, and function of CD4 T cells with special emphasis on HIV target cells (CCR5+ and α4β7+) as well as tissue-resident memory (TRM; CD69+ and CD103+) CD4 T cells in FGT of cycling women. Peripheral blood and Endocervical cells (ECcollected from cytobrush) were collected from 105 healthy women and performed multicolor flow cytometry to characterize the various subsets of CD4 T cells. Cervicovaginal lavage (CVL) were collected for cytokine analysis and plasma were collected for hormonal analysis. All parameters were compared between follicular and luteal phase of menstrual cycle. Results: Our findings revealed no significant difference in the blood CD4 T cell subsets between the follicular and luteal phase. However, in EC, the proportion of several cell types was higher in the follicular phase compared to the luteal phase of menstrual cycle, including CCR5+α4β7-cells (p=0.01), CD69+CD103+ TRM (p=0.02), CCR5+CD69+CD103+ TRM (p=0.001) and FoxP3+ CD4 T cells (p=0.0005). In contrast, α4β7+ CCR5- cells were higher in the luteal phase (p=0.0004) compared to the follicular phase. In addition, we also found that hormonal levels (P4/E2 ratio) and cytokines (IL-5 and IL-6) were correlated with CCR5+ CD4 T cells subsets during the follicular phase of the menstrual cycle Conclusion: Overall, these findings suggest the difference in the expression of CCR5 and α4β7 in TRM CD4 T cell subsets in endocervix of HIV seronegative women between the follicular and luteal phase. Increase in the CCR5+ expression on TRM subsets could increase susceptibility to HIV infection during follicular phase of the menstrual cycle. [ABSTRACT FROM AUTHOR]

Background: Despite the success of antiretroviral therapy (ART), people living with HIV (PLWH) suffer from a high burden of pulmonary diseases, even after accounting for their smoking status. Cytotoxic CD8 T-cells are likely implicated in this phenomenon and may act as a double-edged sword. While being essential in viral infection control, their hyperactivation can also contribute to lung mucosal tissue damage. The effects of HIV and smoking on pulmonary mucosal CD8 T-cell dynamics has been a neglected area of research, which we address herein. Methods: Bronchoalveolar lavage (BAL) fluid were obtained from ART-treated PLWH (median duration of supressed viral load: 9 years; smokers: n = 14; non-smokers: n = 21) and HIV-uninfected controls (smokers: n = 11; non-smokers: n = 20) without any respiratory symptoms or active infection. Lymphocytes were isolated and CD8 T-cell subsets and homing markers were characterized by multiparametric flow cytometry. Results: Both smoking and HIV infection were independently associated with a significant increase in frequencies of total pulmonary mucosal CD8 T-cell. BAL CD8 T-cells were primarily CD69 + expressing CD103 and/or CD49a, at least one of the two granzymes (GzmA/GzmB), and little Perforin. Higher expression levels of CD103, CD69, and GzmB were observed in smokers versus non-smokers. The ex vivo phenotype of GzmA + and GzmB + cells revealed increased expression of CD103 and CXCR6 in smokers, while PLWH displayed elevated levels of CX3CR1 compared to controls. Conclusion: Smoking and HIV could promote cytotoxic CD8 T-cell retention in small airways through different mechanisms. Smoking likely increases recruitment and retention of GzmB + CD8 Trm via CXCR6 and CD103. Heightened CX3CR1 expression could be associated with CD8 non-Trm recruitment from the periphery in PLWH. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint inhibitors (ICIs) have made significant progress in oncotherapy improving survival of patients. However, the benefits are limited to only a small subgroup of patients who could achieve durable responses. Early prediction of response may enable treatment optimization and patient stratification. Therefore, developing appropriate biomarkers is critical to monitoring efficacy and assessing patient response to ICIs. Main body: Herein, we first introduce a new potential biomarker, CD103, expressed on tissue-resident memory T cells, and discuss the potential application of CD103 PET imaging in predicting immune checkpoint inhibitor treatment. In addition, we describe the current targets of ImmunoPET and compare these targets with CD103. To assess the benefit of PET imaging, a comparative analysis between ImmunoPET and other imaging techniques commonly employed for tumor diagnosis was performed. Additionally, we compare ImmunoPET and immunohistochemistry (IHC), a widely utilized clinical method for biomarker identification with respect to visualizing the immune targets. Conclusion: CD103 ImmunoPET is a promising method for determining tumor-infiltrating lymphocytes (TILs) load and response to ICIs, thereby addressing the lack of reliable biomarkers in cancer immunotherapy. Compared to general T cell markers, CD103 is a specific marker for tissue-resident memory T cells, which number increases during successful ICI therapy. ImmunoPET offers noninvasive, dynamic imaging of specific markers, complemented by detailed molecular information from immunohistochemistry (IHC). Radiomics can extract quantitative features from traditional imaging methods, while near-infrared fluorescence (NIRF) imaging aids tumor detection during surgery. In the era of precision medicine, combining such methods will offer a more comprehensive approach to cancer diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Summary: Chronic liver disease results from the orchestrated interplay of components of innate and adaptive immunity in response to liver tissue damage. Recruitment, positioning, and activation of immune cells can contribute to hepatic cell death, inflammation, and fibrogenesis. With disease progression and increasing portal pressure, repeated translocation of bacterial components from the intestinal lumen through the epithelial and vascular barriers leads to persistent mucosal, hepatic, and systemic inflammation which contributes to tissue damage, immune dysfunction, and microbial infection. It is increasingly recognised that innate-like and adaptive T-cell subsets located in the liver, mucosal surfaces, and body cavities play a critical role in the progression of advanced liver disease and inflammatory complications of cirrhosis. Mucosal-associated invariant T cells, natural killer T cells, γδ T cells, and tissue-resident memory T cells in the gut, liver, and ascitic fluid share certain characteristic features, which include that they recognise microbial products, tissue alarmins, cytokines, and stress ligands in tissues, and perform effector functions in chronic liver disease. This review highlights recent advances in the comprehension of human tissue-resident and unconventional T-cell populations and discusses the mechanisms by which they contribute to inflammation, fibrosis, immunosuppression, and antimicrobial surveillance in patients with cirrhosis. Understanding the complex interactions of immune cells in different compartments and their contribution to disease progression will provide further insights for effective diagnostic interventions and novel immunomodulatory strategies in patients with advanced chronic liver disease.

Biological antibodies targeting key cytokines such as IL-17 and IL-23 have revolutionized psoriasis outcome. However, the recurrence remains an urgent challenge to be addressed. Currently, most of the descriptions of skin T-cell characteristics in psoriasis are derived from lesional and non-lesional skin, and their characteristics in resolved lesions (clinically healed lesions) remain vague. In order to further elucidate the cellular mechanism of recurrence, we performed single-cell sequencing and multiplexed immunohistochemical staining of T-cell subsets in autologous resolved lesion (RL), on-site recurrent psoriatic lesion (PL), and adjacent normal-appearing skin (NS) of psoriasis. By comparing with PL and NS tissues, we identified three potential cellular candidates for recurrence in clinically healed lesions: IL-17A/F double producing T cells, unstable Tregs and quiescent TRMs. Our results provide research clues for elucidating the immunological recurrence mechanism of psoriasis, and further work is needed to deepen our findings. [ABSTRACT FROM AUTHOR]

Influenza virus infection is restricted to airway-associated tissues and elicits both cellular and humoral responses ultimately resulting in generation of memory cells able to initiate a rapid immune response against re-infections. Resident memory T cells confer protection at the site of infection where lungresident memory T cells are important for protecting the host against homologous and heterologous influenza virus infections. Mapping kinetics of local and systemic T cell memory formation is needed to better understand the role different T cells have in viral control and protection. After infecting BALB/c mice with influenza virus strain A/Puerto Rico/8/1934 H1N1 the main proportion of activated T cells and B cells expressing the early activation marker CD69 was detected in lungs and lung-draining mediastinal lymph nodes. Increased frequencies of activated cells were also observed in the peripheral lymphoid organs spleen, inguinal lymph nodes and mesenteric lymph nodes. Likewise, antigen-specific T cells were most abundant in lungs and mediastinal lymph nodes but present in all organs studied. CD8+CD103-CD49a+ lung-resident T cells expanded simultaneously with timing of viral clearance whereas CD8+CD103+CD49a+ lung-resident T cells was the most abundant subset after resolution of infection and antigen-specific, lungresident T cells were detected up to seven months after infection. In conclusion, the results in this detailed kinetic study demonstrate that influenza virus infection elicits adaptive immune responses mainly in respiratory tract-associated tissues and that distinct subsets of lung-resident T cells expand at different time points during infection. These findings contribute to the understanding of the adaptive immune response locally and systemically following influenza virus infection and call for further studies on the roles of the lung-resident T cell subsets. [ABSTRACT FROM AUTHOR]

Tertiary lymphoid structure (TLS) and tumor-resident memory T cells (TRM) play crucial roles in the anti-tumor immune response, facilitating a good prognosis in patients with cancer. However, there have been no reports on the relationship between TRM and TLS maturity. In this study, we detected TRM and the maturity of TLS by immunofluorescence staining and analyzed the relationship between their distribution and proportion in patients with lung adenocarcinoma (LUAD). The proportion of TRM within TLSs was significantly higher than that outside and was positively correlated with the survival of patients. In addition, the proportions of CD4+CD103+ TRM and CD8+CD103+ TRM were significantly increased with the gradually maturation of TLSs. We divided the patients into three levels (grade 1, grade 2, and grade 3) according to the presence of increasing maturation of TLSs. The proportion of CD103+ TRM in grade 3 patients was significantly higher than that in grade 1 and grade 2 patients, suggesting a close relationship between CD103+ TRM and TLS maturity. Furthermore, positive prognosis was associated with grade 3 patients that exhibited CD103+ T RM High phenotype. [ABSTRACT FROM AUTHOR]

Immunotherapy against cancer and infectious disease holds the promise of high efficacy with minor side effects. Mucosal vaccines to protect against tumors or infections disease agents that affect the upper airways or the lung are still lacking, however. One mucosal vaccine candidate is the B-subunit of Shiga toxin, STxB. In this review, we compare STxB to other immunotherapy vectors. STxB is a non-toxic protein that binds to a glycosylated lipid, termed globotriaosylceramide (Gb3), which is preferentially expressed by dendritic cells. We review the use of STxB for the cross-presentation of tumor or viral antigens in a MHC class I-restricted manner to induce humoral immunity against these antigens in addition to polyfunctional and persistent CD4+ and CD8+ T lymphocytes capable of protecting against viral infection or tumor growth. Other literature will be summarized that documents a powerful induction of mucosal IgA and resident memory CD8+ T cells against mucosal tumors specifically when STxB-antigen conjugates are administered via the nasal route. It will also be pointed out how STxB-based vaccines have been shown in preclinical cancer models to synergize with other therapeutic modalities (immune checkpoint inhibitors, anti-angiogenic therapy, radiotherapy). Finally, we will discuss how molecular aspects such as low immunogenicity, cross-species conservation of Gb3 expression, and lack of toxicity contribute to the competitive positioning of STxB among the different DC targeting approaches. STxB thereby appears as an original and innovative tool for the development of mucosal vaccines in infectious diseases and cancer. [ABSTRACT FROM AUTHOR]

Protection from liver-stage malaria requires high numbers of CD8+ T cells to find and kill Plasmodium -infected cells. A new malaria vaccine strategy, prime-target vaccination, involves sequential viral-vectored vaccination by intramuscular and intravenous routes to target cellular immunity to the liver. Liver tissue-resident memory (TRM) CD8+ T cells have been shown to be necessary and sufficient for protection against rodent malaria by this vaccine regimen. Ultimately, to most faithfully assess immunotherapeutic responses by these local, specialised, hepatic T cells, periodic liver sampling is necessary, however this is not feasible at large scales in human trials. Here, as part of a phase I/II P. falciparum challenge study of prime-target vaccination, we performed deep immune phenotyping, single-cell RNA-sequencing and kinetics of hepatic fine needle aspirates and peripheral blood samples to study liver CD8+ TRM cells and circulating counterparts. We found that while these peripheral 'TRM-like' cells differed to TRM cells in terms of previously described characteristics, they are similar phenotypically and indistinguishable in terms of key T cell residency transcriptional signatures. By exploring the heterogeneity among liver CD8+ TRM cells at single cell resolution we found two main subpopulations that each share expression profiles with blood T cells. Lastly, our work points towards the potential for using TRM−like cells as a correlate of protection by liver-stage malaria vaccines and, in particular, those adopting a prime-target approach. A simple and reproducible correlate of protection would be particularly valuable in trials of liver-stage malaria vaccines as they progress to phase III, large-scale testing in African infants. We provide a blueprint for understanding and monitoring liver TRM cells induced by a prime-target malaria vaccine approach. [ABSTRACT FROM AUTHOR]

CD8+ T cells are involved in the pathogenesis of inflammatory bowel disease (IBD), a complex multifactorial chronic disease. Here, we present an overview of the current research with the controversial findings of CD8+ T cell subsets and discuss some possible perspectives on their therapeutic value in IBD. Studies on the role of CD8+ T cells in IBD have contradictory outcomes, which might be related to the heterogeneity of the cells. Recent data suggest that cytotoxic CD8+ T cells (Tc1) and interleukin (IL) 17-producing CD8+ (Tc17) cells contribute to the pathogenesis of IBD. Moreover, subsets of regulatory CD8+ T cells are abundant at sites of inflammation and can exhibit pro-inflammatory features. Some subsets of tissue resident memory CD8+ T cells (Trm) might be immunosuppressant, whereas others might be pro-inflammatory. Lastly, exhausted T cells might indicate a positive outcome for patients. The function and plasticity of different subsets of CD8+ T cells in health and IBD remain to be further investigated in a challenging field due to the limited availability of mucosal samples and adequate controls. [ABSTRACT FROM AUTHOR]

Lung-localized CD4 T cells play a critical role in the control of influenza virus infection and can provide broadly protective immunity. However, current influenza vaccination strategies primarily target influenza hemagglutinin (HA) and are administered peripherally to induce neutralizing antibodies. We have used an intranasal vaccination strategy targeting the highly conserved influenza nucleoprotein (NP) to elicit broadly protective lung-localized CD4 T cell responses. The vaccine platform consists of a self-assembling nanolipoprotein particle (NLP) linked to NP with an adjuvant. We have evaluated the functionality, in vivo localization, and persistence of the T cells elicited. Our study revealed that intranasal vaccination elicits a polyfunctional subset of lung-localized CD4 T cells that persist long term. A subset of these lung CD4 T cells localize to the airway, where they can act as early responders following encounter with cognate antigen. Polyfunctional CD4 T cells isolated from airway and lung tissue produce significantly more effector cytokines IFN-y and TNF-α, as well as cytotoxic functionality. When adoptively transferred to naive recipients, CD4 T cells from NLP:NP-immunized lung were sufficient to mediate 100% survival from lethal challenge with H1N1 influenza virus. [ABSTRACT FROM AUTHOR]

• Higher CXCR6+CD4+T cell proportion in pediatric B-ALL patients. • CXCR6 is not a marker of resident memory CD4+ T cells in B-ALL. • CXCR6+CD4+ T cells display enhanced cytotoxicity against B-ALL cells. • CXCR6+CD4+T cells remodel anti-tumor microenvironment. The potential of cytotoxic CD4+ T cells and tissue resident memory T cells (Trm) in achieving adult leukemia remission have been highlighted [1,2]. We hypothesized that CXCR6 could serve as a marker for cytotoxic CD4+ Trm cells in the bone marrow (BM) of pediatric B-ALL patients. Flow cytometry (FCM) and published single cell RNA sequencing (scRNA-seq) datasets were employed to characterize CXCR6+CD4+ T cells in the BM and peripheral blood (PB) of pediatric B-ALL patients and healthy donors. FCM, scRNA-seq and co-culture were utilized to explore the cytotoxicity of CXCR6+CD4+ T cells in vitro based on in vitro induction of CXCR6+CD4+ T cells using tumor antigens and peripheral blood mononuclear cells (PBMCs). The ssGSEA based on the cell markers identified according to the in vivo scRNA-seq data, the TARGET-ALL-P2 datasets, and integrated machine learning algorithm were employed to figure out the key cells with prognostic values, followed by simulation of adoptive cell transfer therapy (ACT). Integrated machine learning identified the high-risk cells for disease free survival, and overall survival, while simulation of ACT therapy using CXCR6+CD4+T cells indicated that CXCR6+CD4+ T cells could remodel the bone marrow microenvironments towards anti-tumor. Based on the expression of genes involved in formation of resident memory T cells, CXCR6 is not a marker of resident memory CD4+T cells but defines therapeutic subtypes of CD4+ cytotoxic T cell lineage for pediatric B-ALL. [ABSTRACT FROM AUTHOR]

Current flu vaccines rely on the induction of strain-specific neutralizing antibodies, which leaves the population vulnerable to drifted seasonal or newly emerged pandemic strains. Therefore, universal flu vaccine approaches that induce broad immunity against conserved parts of influenza have top priority in research. Cross-reactive T cell responses, especially tissue-resident memory T cells in the respiratory tract, provide efficient heterologous immunity, and must therefore be a key component of universal flu vaccines. Here, we review recent findings about T cell-based flu immunity, with an emphasis on tissue-resident memory T cells in the respiratory tract of humans and different animal models. Furthermore, we provide an update on preclinical and clinical studies evaluating T cell-evoking flu vaccines, and discuss the implementation of T cell immunity in real-life vaccine policies.

Abstract: To investigate the role of TCR‐pMHC interaction in regulating lung CD8 tissue‐resident T cell (TR) differentiation, polyclonal responses were compared against NP366‐374/Db and PA224‐233/Db, two immunodominant epitopes that arise during influenza A infection in mice. Memory niches distinct from iBALTs develop within the lamina propria, supporting CD103+ and CD103− CD8 TR generation and intraepithelial translocation. Gene set enrichment analysis (GSEA) and weighted gene co‐expression network analysis (WGCNA) identify dominant TCR, adherens junction, RIG‐I‐like and NOD‐like pattern recognition receptor as well as TGF‐β signaling pathways and memory signatures among PA224‐233/Db T cells consistent with T resident memory (TRM) status. In contrast, NP366‐374/Db T cells exhibit enrichment of effector signatures, upregulating pro‐inflammatory mediators even among TRM. While NP366‐374/Db T cells manifest transcripts linked to canonical exhaustion pathways, PA224‐233/Db T cells exploit P2rx7 purinoreceptor attenuation. The NP366‐374/Db CD103+ subset expresses the antimicrobial lactotransferrin whereas PA224‐233/Db CD103+ utilizes pore‐forming mpeg‐1, with <22% of genes correspondingly upregulated in CD103+ (or CD103−) subsets of both specificities. Thus, TCR‐pMHC interactions among TR and antigen presenting cells in a tissue milieu strongly impact CD8 T cell biology. [ABSTRACT FROM AUTHOR]

Abstract: Allogeneic hematopoietic cell transplantation (HCT), but not autologous HCT, can provide long-term remission in some patients with adult T cell leukemia-lymphoma (ATL). We retrospectively analyzed the effects of acute graft-versus-host disease (GVHD) among the 616 patients with ATL who survived at least 30 days after allogeneic HCT with other than cord blood grafts. Multivariate analyses treating the occurrence of GVHD as a time-varying covariate demonstrated an association between grade I-II acute GVHD and favorable overall survival (OS) (hazard ratio [HR], 0.634; 95% confidence interval [CI], 0.477 to 0.843), whereas grade III-IV acute GVHD showed a trend toward unfavorable OS (HR, 1.380; 95% CI, 0.988 to 1.927) compared with nonacute GVHD. In subsequent multivariate analyses of patients who survived at least 100 days after HCT (n = 431), the presence of limited chronic GVHD showed a trend toward favorable OS (HR, 0.597; 95% CI, 0.354 to 1.007), and extensive chronic GVHD had a significant effect on OS (HR, 0.585; 95% CI, 0.389 to 0.880). There were no significant interactions between myeloablative conditioning or reduced-intensity conditioning with OS even when acute GVHD was absent or present at grade I-II or grade III-IV or when chronic GVHD was absent, limited, or extensive. This study demonstrates the actual existence of graft-versus-ATL effects in patients with ATL regardless of whether myeloablative conditioning or reduced-intensity conditioning is used. [Copyright &y& Elsevier]

The nature of the anti-tumor immune response changes as primary tumors progress and metastasize. We investigated the role of resident memory (Trm) and circulating memory (Tcirm) cells in anti-tumor responses at metastatic locations using a mouse model of melanoma-associated vitiligo. We found that the transcriptional characteristics of tumor-specific CD8+ T cells were defined by the tissue of occupancy. Parabiosis revealed that tumor-specific Trm and Tcirm compartments persisted throughout visceral organs, but Trm cells dominated lymph nodes (LNs). Single-cell RNA-sequencing profiles of Trm cells in LN and skin were distinct, and T cell clonotypes that occupied both tissues were overwhelmingly maintained as Trm in LNs. Whereas Tcirm cells prevented melanoma growth in the lungs, Trm afforded long-lived protection against melanoma seeding in LNs. Expanded Trm populations were also present in melanoma-involved LNs from patients, and their transcriptional signature predicted better survival. Thus, tumor-specific Trm cells persist in LNs, restricting metastatic cancer. [Display omitted] • Tissue localization defines the transcriptional profile of tumor-specific CD8+ T cells • Melanoma-specific Trm populations develop in skin-draining lymph nodes • Trm cells protect against melanoma tumor seeding in lymph nodes • A lymph node Trm transcriptional signature uniquely predicts survival in melanoma patients Lymph nodes (LNs) are frequent sites of metastasis. Molodtsov, Khatwani et al. find that melanoma-specific CD8+ T cells persist as functional resident memory (Trm) populations within skin-draining LNs, and these Trm cells prevent melanoma growth upon tumor seeding in LNs. A LN Trm transcriptional signature predicts survival in melanoma patients, highlighting the relevance of LN Trm function in human disease. [ABSTRACT FROM AUTHOR]

In health, the non-recirculating nature and long-term persistence of tissue-resident memory T cells (TRMs) in tissues protects against invading pathogens. In disease, pathogenic TRMs contribute to the recurring traits of many skin diseases. We aimed to conduct a systematic literature review on the current understanding of the role of TRMs in skin diseases and identify gaps as well as future research paths. EMBASE, PubMed, SCOPUS, Web of Science, Clinicaltrials.gov and WHO Trials Registry were searched systematically for relevant studies from their inception to October 2020. Included studies were reviewed independently by two authors. This study was conducted in accordance with the PRISMA-S guidelines. This protocol was registered with the PROSPERO database (ref: CRD42020206416). We identified 96 studies meeting the inclusion criteria. TRMs have mostly been investigated in murine skin and in relation to infectious skin diseases. Pathogenic TRMs have been characterized in various skin diseases including psoriasis, vitiligo and cutaneous T-cell lymphoma. Studies are needed to discover biomarkers that may delineate TRMs poised for pathogenic activity in skin diseases and establish to which extent TRMs are contingent on the local skin microenvironment. Additionally, future studies may investigate the effects of current treatments on the persistence of pathogenic TRMs in human skin. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) often develops following chronic hepatitis B virus (HBV) infection and responds poorly to immune checkpoint blockade. Here, we examined the antigen specificities of HCC-infiltrating T cells and their relevance to tumor control. Using highly multiplexed peptide-MHC tetramer staining of unexpanded cells from blood, liver, and tumor tissues from 46 HCC patients, we detected 91 different antigen-specific CD8+ T cell populations targeting HBV, neoantigen, tumor-associated, and disease-unrelated antigens. Parallel high-dimensional analysis delineated five distinct antigen-specific tissue-resident memory T (Trm) cell populations. Intratumoral and intrahepatic HBV-specific T cells were enriched for two Trm cell subsets that were PD-1lo TOX lo, despite being clonally expanded. High frequencies of intratumoral terminally exhausted T cells were uncommon. Patients with tumor-infiltrating HBV-specific CD8+ Trm cells exhibited longer-term relapse-free survival. Thus, non-terminally exhausted HBV-specific CD8+ Trm cells show hallmarks of active involvement and effective antitumor response, implying that these cells could be harnessed for therapeutic purposes. [Display omitted] • Broad analysis of CD8+ T cell antigen specificity in HBV-HCC patient blood, liver, tumor • Tumor-infiltrating HBV-specific T cells correlate with superior relapse-free survival • Five Trm subsets are enriched in liver- and tumor-infiltrating HBV-specific T cells • HBV-specific Trm cells have expanded TCR clones and lack hallmarks of terminal exhaustion Hepatocellular carcinoma (HCC) often develops following chronic hepatitis B virus (HBV) infection and responds poorly to immune checkpoint blockade. Cheng et al. examine the antigen specificities of HCC-infiltrating T cells and reveal that HBV-specific Trm cells are phenotypically distinct, clonally expanded, and are not terminally exhausted, suggesting that these cells may be harnessed for therapeutic purposes. [ABSTRACT FROM AUTHOR]

Current flu vaccines rely on the induction of strain-specific neutralizing antibodies, which leaves the population vulnerable to drifted seasonal or newly emerged pandemic strains. Therefore, universal flu vaccine approaches that induce broad immunity against conserved parts of influenza have top priority in research. Cross-reactive T cell responses, especially tissue-resident memory T cells in the respiratory tract, provide efficient heterologous immunity, and must therefore be a key component of universal flu vaccines. Here, we review recent findings about T cell-based flu immunity, with an emphasis on tissue-resident memory T cells in the respiratory tract of humans and different animal models. Furthermore, we provide an update on preclinical and clinical studies evaluating T cell-evoking flu vaccines, and discuss the implementation of T cell immunity in real-life vaccine policies. [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs) are antigen-presenting cells controlling T cell activation. In humans, the diversity, ontogeny, and functional capabilities of DC subsets are not fully understood. Here, we identified circulating CD88−CD1c+CD163+ DCs (called DC3s) as immediate precursors of inflammatory CD88−CD14+CD1c+CD163+FcεRI+ DCs. DC3s develop via a specific pathway activated by GM-CSF, independent of cDC-restricted (CDP) and monocyte-restricted (cMoP) progenitors. Like classical DCs but unlike monocytes, DC3s drove activation of naive T cells. In vitro , DC3s displayed a distinctive ability to prime CD8+ T cells expressing a tissue homing signature and the epithelial homing alpha-E integrin (CD103) through transforming growth factor β (TGF-β) signaling. In vivo , DC3s infiltrated luminal breast cancer primary tumors, and DC3 infiltration correlated positively with CD8+CD103+CD69+ tissue-resident memory T cells. Together, these findings define DC3s as a lineage of inflammatory DCs endowed with a strong potential to regulate tumor immunity. • DC3s are phenotypic and functional intermediates between cDC2s and monocytes • GM-CSF alone, but not FLT3L, supports efficient differentiation of DC3s • DC3s do not differentiate via cDC (CDP)- or monocyte-restricted (cMoP) progenitors • DC3s prime T RM cells in vitro and correlate with T RM expansion in primary breast cancer Bourdely et al. identify human CD88−CD1c+CD163+ DC3s as a pro-inflammatory phagocyte lineage sharing features with monocytes and conventional DCs. DC3s efficiently induce differentiation of CD103+CD8+ T cells in vitro , and their infiltration correlates with CD8+CD69+CD103+ T RM accumulation in breast tumors. [ABSTRACT FROM AUTHOR]

Checkpoint blockade with antibodies specific for the PD-1 and CTLA-4 inhibitory receptors can induce durable responses in a wide range of human cancers. However, the immunological mechanisms responsible for severe inflammatory side effects remain poorly understood. Here we report a comprehensive single-cell analysis of immune cell populations in colitis, a common and severe side effect of checkpoint blockade. We observed a striking accumulation of CD8 T cells with highly cytotoxic and proliferative states and no evidence of regulatory T cell depletion. T cell receptor (TCR) sequence analysis demonstrated that a substantial fraction of colitis-associated CD8 T cells originated from tissue-resident populations, explaining the frequently early onset of colitis symptoms following treatment initiation. Our analysis also identified cytokines, chemokines, and surface receptors that could serve as therapeutic targets for colitis and potentially other inflammatory side effects of checkpoint blockade. • Mechanisms of inflammatory adverse events induced by checkpoint blockade • Colitis-associated differentiation of CD8 Trm cells to cytotoxic effector cells • Persistence and expansion of CTLA-4+ Treg cells • Inflammatory pathways provide opportunities for therapeutic intervention Single-cell analyses of immune checkpoint blockade-associated colitis patient samples reveal enrichment of regulatory T cells in colitic lesions and nominate inflammatory pathways for potential therapeutic intervention. [ABSTRACT FROM AUTHOR]

• T cells are critical for protective immunity but can also induce graft rejection. • T cell differentiation is primarily regulated by intrinsic transcriptional pathways. • New reports suggest that context-dependent T cell differentiation programs exist. • Recent advances and implications for transplantation will be discussed. • Specifically, IRF4, Tbet/Eomes and regulation of tissue-resident memory cells (Trm). • Understanding these pathways may aid the development of novel anti-rejection therapies. While T cells play a critical role in protective immunity against infection, they are also responsible for graft rejection in the setting of transplantation. T cell differentiation is regulated by both intrinsic transcriptional pathways as well as extrinsic factors such as antigen encounter and the cytokine milieu. Herein, we review recent discoveries in the transcriptional regulation of T cell differentiation and their impact on the field of transplantation. Recent studies uncovering context-dependent differentiation programs that differ in the setting of infection or transplantation will also be discussed. Understanding the key transcriptional pathways that underlie T cell responses in transplantation has important clinical implications, including development of novel therapeutic agents to mitigate graft rejection. [ABSTRACT FROM AUTHOR]