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Long-lived tissue-resident memory T cells (T RM cells) confer fast, robust protection after pathogen rechallenge. Gebhardt and colleagues show that skin T RM cells arise from KLRG1 – cells that differentiate in situ in response to IL-15 and TGF-β. Tissue-resident memory T cells (T RM cells) provide superior protection against infection in extralymphoid tissues. Here we found that CD103 + CD8 + T RM cells developed in the skin from epithelium-infiltrating precursor cells that lacked expression of the effector-cell marker KLRG1. A combination of entry into the epithelium plus local signaling by interleukin 15 (IL-15) and transforming growth factor-β (TGF-β) was required for the formation of these long-lived memory cells. Notably, differentiation into T RM cells resulted in the progressive acquisition of a unique transcriptional profile that differed from that of circulating memory cells and other types of T cells that permanently reside in skin epithelium. We provide a comprehensive molecular framework for the local differentiation of a distinct peripheral population of memory cells that forms a first-line immunological defense system in barrier tissues.

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.

The Immunological Genome Project aims to build a comprehensive database of gene-expression and gene-regulatory networks in the mouse immune system. Here Turley and colleagues analyze the transcriptomes of lymph-node stromal cells under steady-state and inflammatory conditions. Lymph node stromal cells (LNSCs) closely regulate immunity and self-tolerance, yet key aspects of their biology remain poorly elucidated. Here, comparative transcriptomic analyses of mouse LNSC subsets demonstrated the expression of important immune mediators, growth factors and previously unknown structural components. Pairwise analyses of ligands and cognate receptors across hematopoietic and stromal subsets suggested a complex web of crosstalk. Fibroblastic reticular cells (FRCs) showed enrichment for higher expression of genes relevant to cytokine signaling, relative to their expression in skin and thymic fibroblasts. LNSCs from inflamed lymph nodes upregulated expression of genes encoding chemokines and molecules involved in the acute-phase response and the antigen-processing and antigen-presentation machinery. Poorly studied podoplanin (gp38)-negative CD31 − LNSCs showed similarities to FRCs but lacked expression of interleukin 7 (IL-7) and were identified as myofibroblastic pericytes that expressed integrin α 7 . Together our data comprehensively describe the transcriptional characteristics of LNSC subsets.

The progenitor stage of commitment toward the conventional dendritic cell subsets and the transcriptional networks that control it remain poorly understood. Two articles from Ginhoux and colleagues and Murphy and colleagues offer insight into these processes. Mouse conventional dendritic cells (cDCs) can be classified into two functionally distinct lineages: the CD8α + (CD103 + ) cDC1 lineage, and the CD11b + cDC2 lineage. cDCs arise from a cascade of bone marrow (BM) DC-committed progenitor cells that include the common DC progenitors (CDPs) and pre-DCs, which exit the BM and seed peripheral tissues before differentiating locally into mature cDCs. Where and when commitment to the cDC1 or cDC2 lineage occurs remains poorly understood. Here we found that transcriptional signatures of the cDC1 and cDC2 lineages became evident at the single-cell level from the CDP stage. We also identified Siglec-H and Ly6C as lineage markers that distinguished pre-DC subpopulations committed to the cDC1 lineage (Siglec-H − Ly6C − pre-DCs) or cDC2 lineage (Siglec-H − Ly6C + pre-DCs). Our results indicate that commitment to the cDC1 or cDC2 lineage occurs in the BM and not in the periphery.

Tissue-resident memory T cells (T RM cells) provide rapid frontline protection from reinfection. Bergsbaken and Bevan identify a gut T RM cell population generated via an unconventional pathway that is protective against a natural mouse intestinal pathogen. We report that oral infection with Yersinia pseudotuberculosis results in the development of two distinct populations of pathogen-specific CD8 + tissue-resident memory T cells (T RM cells) in the lamina propria. CD103 − T cells did not require transforming growth factor-β (TGF-β) signaling but were true resident memory cells. Unlike CD103 + CD8 + T cells, which were TGF-β dependent and were scattered in the tissue, CD103 − CD8 + T cells clustered with CD4 + T cells and CX3CR1 + macrophages and/or dendritic cells around areas of bacterial infection. CXCR3-dependent recruitment of cells to inflamed areas was critical for development of the CD103 − population and pathogen clearance. Our studies have identified the 'preferential' development of CD103 − T RM cells in inflammatory microenvironments within the lamina propria and suggest that this subset has a critical role in controlling infection.

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.

Dendritic cells (DCs) that orchestrate mucosal immunity have been studied in mice. Lahl and colleagues characterize human gut DC populations and define their relationship to previously described human and mouse DCs. Dendritic cells (DCs) that orchestrate mucosal immunity have been studied in mice. Here we characterized human gut DC populations and defined their relationship to previously studied human and mouse DCs. CD103 + Sirpα − DCs were related to human blood CD141 + DCs and to mouse intestinal CD103 + CD11b − DCs and expressed markers of cross-presenting DCs. CD103 + Sirpα + DCs aligned with human blood CD1c + DCs and mouse intestinal CD103 + CD11b + DCs and supported the induction of regulatory T cells. Both CD103 + DC subsets induced the T H 17 subset of helper T cells, while CD103 − Sirpα + DCs induced the T H 1 subset of helper T cells. Comparative analysis of transcriptomes revealed conserved transcriptional programs among CD103 + DC subsets and identified a selective role for the transcriptional repressors Bcl-6 and Blimp-1 in the specification of CD103 + CD11b − DCs and intestinal CD103 + CD11b + DCs, respectively. Our results highlight evolutionarily conserved and divergent programming of intestinal DCs.

Few studies implicate immunoregulatory gene expression in tumor cells in arbitrating brain tumor progression. Here we show that fibrinogen-like protein 2 (FGL2) is highly expressed in glioma stem cells and primary glioblastoma (GBM) cells. FGL2 knockout in tumor cells did not affect tumor-cell proliferation in vitro or tumor progression in immunodeficient mice but completely impaired GBM progression in immune-competent mice. This impairment was reversed in mice with a defect in dendritic cells (DCs) or CD103 + DC differentiation in the brain and in tumor-draining lymph nodes. The presence of FGL2 in tumor cells inhibited granulocyte-macrophage colony-stimulating factor (GM-CSF)-induced CD103 + DC differentiation by suppressing NF-κB, STAT1/5, and p38 activation. These findings are relevant to GBM patients because a low level of FGL2 expression with concurrent high GM-CSF expression is associated with higher CD8B expression and longer survival. These data provide a rationale for therapeutic inhibition of FGL2 in brain tumors. Fibrinogen-like protein 2 (FGL2) mediates immune suppression in glioblastoma (GBM). Here, the authors show that FGL-2 expressed by GBM cancer cells acts by suppressing the differentiation of CD103+ DC cells required to activate the anti-tumor CD8+ T cell response via blocking GM-CSF signalling at NFKB, STAT1/5 and p38 level.

The brain is not routinely surveyed by lymphocytes and is defined as an immuno-privileged site. However, viral infection of the brain results in the infiltration and long-term persistence of pathogen-specific CD8⁺ T cells. These cells survive without replenishment from the circulation and are referred to as resident memory T cells (Trm). Brain Trm selectively express the integrin CD103, the expression of which is dependent on antigen recognition within the tissue. After clearance of virus, CD8⁺ T cells persist in tight clusters, presumably at prior infection hot spots. Antigen persistence is not a prerequisite for T-cell retention, as suggested by the failure to detect viral genomes in the T-cell clusters. Furthermore, we show that an intracranial dendritic cell immunization regimen, which allows the transient introduction of antigen, also results in the generation of memory T cells that persist long term in the brain. Brain Trm die rapidly on isolation from the tissue and fail to undergo recall expansion after adoptive transfer into the blood-stream of antigen-challenged recipients. These ex vivo defects imply a dependency on the local milieu for function and survival. Cumulatively, this work shows that Trm are a specialized population of memory T cells that can be deposited in tissues previously thought to be beyond routine immune surveillance.

The functions of individual dendritic cell subsets in the skin are unclear. Heath and colleagues now show that langerin-positive CD103 + dermal dendritic cells are the main migratory subtype able to cross-present antigen. Skin-derived dendritic cells (DCs) include Langerhans cells, classical dermal DCs and a langerin-positive CD103 + dermal subset. We examined their involvement in the presentation of skin-associated viral and self antigens. Only the CD103 + subset efficiently presented antigens of herpes simplex virus type 1 to naive CD8 + T cells, although all subsets presented these antigens to CD4 + T cells. This showed that CD103 + DCs were the migratory subset most efficient at processing viral antigens into the major histocompatibility complex class I pathway, potentially through cross-presentation. This was supported by data showing only CD103 + DCs efficiently cross-presented skin-derived self antigens. This indicates CD103 + DCs are the main migratory subtype able to cross-present viral and self antigens, which identifies another level of specialization for skin DCs.