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Tissue-resident memory CD8 T (TRM) cells are a unique immune memory subset that develops and remains in peripheral tissues at the site of infection, providing future host resistance upon reexposure to that pathogen. In the pulmonary system, TRM are identified through S1P antagonist CD69 and expression of integrins CD103/β7 and CD49a/CD29(β1). Contrary to the established role of CD69 on CD8 T cells, the functions of CD103 and CD49a on this population are not well defined. This study examines the expression patterns and functions of CD103 and CD49a with a specific focus on their impact on T cell motility during influenza virus infection. We show that the TRM cell surface phenotype develops by 2 wk postinfection, with the majority of the population expressing CD49a and a subset that is also positive for CD103. Despite a previously established role in retaining TRM in peripheral tissues, CD49a facilitates locomotion of virus-specific CD8 T cells, both in vitro and in vivo. These results demonstrate that CD49a may contribute to local surveillance mechanisms of the TRM population.

Background Clear cell renal cell carcinoma (CCRCC) is characterized by a highly metastatic potential. The stromal communication between stem cells and cancer cells critically influences metastatic dissemination of cancer cells. Methods The effect of exosomes isolated from cancer stem cells (CSCs) of CCRCC patients on the progress of epithelial-mesenchymal transition (EMT) and lung metastasis of CCRCC cells were examined. Results CSCs exosomes promoted proliferation of CCRCC cells and accelerated the progress of EMT. Bioactive miR-19b-3p transmitted to cancer cells by CSC exosomes induced EMT via repressing the expression of PTEN. CSCs exosomes derived from CCRCC patients with lung metastasis produced the strongest promoting effect on EMT. Notably, CD103 + CSC exosomes were enriched in tumor cells and in lung as well, highlighting the organotropism conferred by CD103. In addition, CD103 + exosomes were increased in blood samples from CCRCC patients with lung metastasis. Conclusions CSC exosomes transported miR-19b-3p into CCRCC cells and initiated EMT promoting metastasis. CD103 + acted to guide CSC exosomes to target cancer cells and organs, conferring the higher metastatic capacity of CCRCC to lungs, suggesting CD103 + exosomes as a potential metastatic diagnostic biomarker. Graphical abstract ᅟ

Non-alcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease that can progress to liver fibrosis. Recent clinical advance suggests a reversibility of liver fibrosis, but the cellular and molecular mechanisms underlying NASH resolution remain unclarified. Here, using a murine diet-induced NASH and the subsequent resolution model, we demonstrate direct roles of CD8 + tissue-resident memory CD8 + T (CD8 + Trm) cells in resolving liver fibrosis. Single-cell transcriptome analysis and FACS analysis revealed CD69 + CD103 − CD8 + Trm cell enrichment in NASH resolution livers. The reduction of liver CD8 + Trm cells, maintained by tissue IL-15, significantly delayed fibrosis resolution, while adoptive transfer of these cells protected mice from fibrosis progression. During resolution, CD8 + Trm cells attracted hepatic stellate cells (HSCs) in a CCR5-dependent manner, and predisposed activated HSCs to FasL-Fas-mediated apoptosis. Histological assessment of patients with NASH revealed CD69 + CD8 + Trm abundance in fibrotic areas, further supporting their roles in humans. These results highlight the undefined role of liver CD8 + Trm in fibrosis resolution. The cellular and molecular mechanisms underlying the resolution of non-alcoholic steatohepatitis remain incompletely understood. Here the authors report a single cell-based analysis that identified CD8 + tissue-resident memory T cells, which contribute to resolution of liver fibrosis potentially via elimination of hepatic stellate cells through Fas-mediated cytotoxicity.

The clinical success of cancer immune checkpoint blockade (ICB) has refocused attention on tumor-infiltrating lymphocytes (TILs) across cancer types. The outcome of immune checkpoint inhibitor therapy in cancer patients has been linked to the quality and magnitude of T cell, NK cell, and more recently, B cell responses within the tumor microenvironment. State-of-the-art single-cell analysis of TIL gene expression profiles and clonality has revealed a remarkable degree of cellular heterogeneity and distinct patterns of immune activation and exhaustion. Many of these states are conserved across tumor types, in line with the broad responses observed clinically. Despite this homology, not all cancer types with similar TIL landscapes respond similarly to immunotherapy, highlighting the complexity of the underlying tumor-immune interactions. This observation is further confounded by the strong prognostic benefit of TILs observed for tumor types that have so far respond poorly to immunotherapy. Thus, while a holistic view of lymphocyte infiltration and dysfunction on a single-cell level is emerging, the search for response and prognostic biomarkers is just beginning. Within this review, we discuss recent advances in the understanding of TIL biology, their prognostic benefit, and their predictive value for therapy.The schematic representation of the tumor immune environment shows the composition and function of a tertiary lymphoid structures (TLS), who are usually found peritumorally in the stroma and/or in the invasive margin. The chemokine CXCL13, produced by CD8+ T cells, induces chemotaxis by binding to the receptor CXCR5, mainly expressed by B cells and TFH cells, and regulates the organization of B cells inside the follicles of lymphoid tissues. The TLS consists out of a T cell-rich zone containing mature dendritic cells (DCs), in close proximity to GC containing follicle like-B cells, intermingled with follicular dendritic cells (FDCs) and surrounded by plasma cells and helper-innate lymphoid cell group 3 (ILC3) at the edge of the TLS. In the optimally organized TLS immune structure, DCs, FDCs, T cells and B cells interact and activate each other, promoting a local sustained immune response including the induction of T cell effector function, antibody generation, and clonal expansion. The stroma surrounding the tumor epithelium and the invasive margin further harbors cellular immune components including NK cells, macrophages, ILC1s and ILC2s, and a nonimmune cellular component, including fibroblasts. Within the tumor epithelium ILCs, NK cells, B cells, and different T cell subsets are present, including TEX cells,-tumor-specific CD103+CD39+ TRM CTLs and CD103+CD39- bystander TRM cells. Upon ICB, both T and B cell signaling increases. TCF1-expressing TPE cells expand and differentiate into TRM cells migrating to the tumor, where they can exert their cytolytic potential. The ICB response also increases B cell receptor diversity by means of SMH and CSR and induces their clonal expansion and differentiation into advanced antibody-producing plasma cells. TLS: tertiary lymphoid structure, TFH cells: follicular helper T cells, DCs: dendritic cells, GC: germinal center, FDCs: follicular dendritic cells, ILC3: helper-innate lymphoid cell group 3, NK cells: natural killer cells, ILC1: helper-innate lymphoid cell group 1, ILC2: helper-innate lymphoid cell group 2, TEX: terminally exhausted T cells, CTLs: cytotoxic lymphocytes, TRM: tissue resident memory, ICB: immune checkpoint blockade, TCF1: transcription factor 1, TPE: progenitor STEM-like exhausted cells, SMH: somatic hypermutation, RCS: recombinant class switch

Identifying tumor antigen-specific T cells from cancer patients has important implications for immunotherapy diagnostics and therapeutics. Here, we show that CD103 + CD39 + tumor-infiltrating CD8 T cells (CD8 TIL) are enriched for tumor-reactive cells both in primary and metastatic tumors. This CD8 TIL subset is found across six different malignancies and displays an exhausted tissue-resident memory phenotype. CD103 + CD39 + CD8 TILs have a distinct T-cell receptor (TCR) repertoire, with T-cell clones expanded in the tumor but present at low frequencies in the periphery. CD103 + CD39 + CD8 TILs also efficiently kill autologous tumor cells in a MHC-class I-dependent manner. Finally, higher frequencies of CD103 + CD39 + CD8 TILs in patients with head and neck cancer are associated with better overall survival. Our data thus describe an approach for detecting tumor-reactive CD8 TILs that will help define mechanisms of existing immunotherapy treatments, and may lead to future adoptive T-cell cancer therapies. Identifying and enumerating tumor-specific CD8 T cells are important for assessing cancer prognosis and therapy efficacy. Here the authors show that CD39 and CD103 mark a subset of tumor-infiltrating CD8 T cells that are tumor-reactive and exhibit characteristics of exhausted or tissue-resident memory T cells.

There is a growing appreciation for the importance of the gut microbiota as a therapeutic target in various diseases. However, there are only a handful of known commensal strains that can potentially be used to manipulate host physiological functions. Here we isolate a consortium of 11 bacterial strains from healthy human donor faeces that is capable of robustly inducing interferon-γ-producing CD8 T cells in the intestine. These 11 strains act together to mediate the induction without causing inflammation in a manner that is dependent on CD103 + dendritic cells and major histocompatibility (MHC) class Ia molecules. Colonization of mice with the 11-strain mixture enhances both host resistance against Listeria monocytogenes infection and the therapeutic efficacy of immune checkpoint inhibitors in syngeneic tumour models. The 11 strains primarily represent rare, low-abundance components of the human microbiome, and thus have great potential as broadly effective biotherapeutics. A consortium of 11 bacterial strains from the healthy human gut microbiota can strongly induce interferon-γ-producing CD8 T cells in the intestine, and enhance both resistance to bacterial infection and the therapeutic efficacy of immune checkpoint inhibitors.

Most tissues are populated by tissue-resident memory T cells (T RM cells), which are adapted to their niche and appear to be indispensable for local protection against pathogens. Here we show that human white matter-derived brain CD8 + T cells can be subsetted into CD103 − CD69 + and CD103 + CD69 + T cells both with a phenotypic and transcription factor profile consistent with T RM cells. Specifically, CD103 expression in brain CD8 + T cells correlates with reduced expression of differentiation markers, increased expression of tissue-homing chemokine receptors, intermediate and low expression of the transcription factors T-bet and eomes, increased expression of PD-1 and CTLA-4, and low expression of cytolytic enzymes with preserved polyfunctionality upon activation. Brain CD4 + T cells also display T RM cell-associated markers but have low CD103 expression. We conclude that the human brain is surveilled by T RM cells, providing protection against neurotropic virus reactivation, whilst being under tight control of key immune checkpoint molecules. Tissue-resident immune cells are important for local protections from pathogens. Here the authors show that brain tissue-resident memory T cells (T RM  cells) can be further subsetted by CD103 expression, with higher CD103 correlates with increased chemokine receptor and exhaustion markers such as PD1 or CTLA4, but reduced differentiation markers.

Tissue-resident memory T (T RM ) cells are non-recirculating cells that exist throughout the body. Although T RM cells in various organs rely on common transcriptional networks to establish tissue residency, location-specific factors adapt these cells to their tissue of lodgment. Here we analyze T RM cell heterogeneity between organs and find that the different environments in which these cells differentiate dictate T RM cell function, durability and malleability. We find that unequal responsiveness to TGFβ is a major driver of this diversity. Notably, dampened TGFβ signaling results in CD103 − T RM cells with increased proliferative potential, enhanced function and reduced longevity compared with their TGFβ-responsive CD103 + T RM counterparts. Furthermore, whereas CD103 − T RM cells readily modified their phenotype upon relocation, CD103 + T RM cells were comparatively resistant to transdifferentiation. Thus, despite common requirements for T RM cell development, tissue adaptation of these cells confers discrete functional properties such that T RM cells exist along a spectrum of differentiation potential that is governed by their local tissue microenvironment. Tissue-resident memory T (T RM ) cells are distributed throughout the body as relatively sessile populations. Mackay and colleagues find that the tissue in which T RM cells are generated dictates their properties and is in turn defined according to T RM -cell-intrinsic sensitivity to signaling via the cytokine TGFβ.

A goal of vaccination is to elicit and maintain tissue-resident memory T cells. Amsen and colleagues show human lung-resident memory CD8 + T cells express distinct transcriptional programs, including a role for Notch in cellular metabolism and maintenance. Tissue-resident memory T cells (T RM cells) in the airways mediate protection against respiratory infection. We characterized T RM cells expressing integrin α E (CD103) that reside within the epithelial barrier of human lungs. These cells had specialized profiles of chemokine receptors and adhesion molecules, consistent with their unique localization. Lung T RM cells were poised for rapid responsiveness by constitutive expression of deployment-ready mRNA encoding effector molecules, but they also expressed many inhibitory regulators, suggestive of programmed restraint. A distinct set of transcription factors was active in CD103 + T RM cells, including Notch. Genetic and pharmacological experiments with mice revealed that Notch activity was required for the maintenance of CD103 + T RM cells. We have thus identified specialized programs underlying the residence, persistence, vigilance and tight control of human lung T RM cells.

Induction of tumor cell death is the therapeutic goal for most anticancer drugs. Yet, a mode of drug-induced cell death, known as immunogenic cell death (ICD), can propagate antitumoral immunity to augment therapeutic efficacy. Currently, the molecular hallmark of ICD features the release of damage-associated molecular patterns (DAMPs) by dying cancer cells. Here, we show that gemcitabine, a standard chemotherapy for various solid tumors, triggers hallmark immunostimualtory DAMP release (e.g., calreticulin, HSP70, and HMGB1); however, is unable to induce ICD. Mechanistic studies reveal gemcitabine concurrently triggers prostaglandin E 2 release as an inhibitory DAMP to counterpoise the adjuvanticity of immunostimulatory DAMPs. Pharmacological blockade of prostaglandin E 2 biosythesis favors CD103 + dendritic cell activation that primes a Tc1-polarized CD8 + T cell response to bolster tumor rejection. Herein, we postulate that an intricate balance between immunostimulatory and inhibitory DAMPs could determine the outcome of drug-induced ICD and pose COX-2/prostaglandin E 2 blockade as a strategy to harness ICD. Most chemotherapeutic agents, including gemcitabine, do not elicit immunogenic cell death, a phenomenon associated with the release of damage-associated molecule patterns (DAMPs). Here, the authors show that gemcitabine-treated dying cancer cells express hallmark DAMPs but their immunogenic properties are hindered by the concomitant release of the inhibitory DAMP PGE 2 .