Retinoic acid and TGF-β orchestrate organ-specific programs of tissue residency.

Tissue-resident memory T (T) cells are integral to tissue immunity, persisting in diverse anatomical sites where they adhere to a common transcriptional framework. How these cells integrate distinct local cues to adopt the common T cell fate remains poorly understood. Here, we show that whereas skin T cells strictly require transforming growth factor β (TGF-β) for tissue residency, those in other locations utilize the metabolite retinoic acid (RA) to drive an alternative differentiation pathway, directing a TGF-β-independent tissue residency program in the liver and synergizing with TGF-β to drive T cells in the small intestine.

The Multifaceted Role of Tissue-Resident Memory T Cells.

Regionalized immune surveillance relies on the concerted efforts of diverse memory T cell populations. Of these, tissue-resident memory T (T) cells are strategically positioned in barrier tissues, where they enable efficient frontline defense against infections and cancer. However, the long-term persistence of these cells has been implicated in a variety of immune-mediated pathologies.

Divergent molecular networks program functionally distinct CD8 skin-resident memory T cells.

Skin-resident CD8 T cells include distinct interferon-γ-producing [tissue-resident memory T type 1 (T1)] and interleukin-17 (IL-17)-producing (T17) subsets that differentially contribute to immune responses. However, whether these populations use common mechanisms to establish tissue residence is unknown. In this work, we show that T1 and T17 cells navigate divergent trajectories to acquire tissue residency in the skin.

Serotonin reduction in post-acute sequelae of viral infection.

Post-acute sequelae of COVID-19 (PASC, "Long COVID") pose a significant global health challenge. The pathophysiology is unknown, and no effective treatments have been found to date. Several hypotheses have been formulated to explain the etiology of PASC, including viral persistence, chronic inflammation, hypercoagulability, and autonomic dysfunction.

Stem-like exhausted and memory CD8 T cells in cancer.

T cells can acquire a broad spectrum of differentiation states following activation. At the extreme ends of this continuum are short-lived cells equipped with effector machinery and more quiescent, long-lived cells with heightened proliferative potential and stem cell-like developmental plasticity. The latter encompass stem-like exhausted T cells and memory T cells, both of which have recently emerged as key determinants of cancer immunity and response to immunotherapy.

Single-cell protein expression profiling resolves circulating and resident memory T cell diversity across tissues and infection contexts.

Memory CD8 T cells can be broadly divided into circulating (T) and tissue-resident memory T (T) populations. Despite well-defined migratory and transcriptional differences, the phenotypic and functional delineation of T and T cells, particularly across tissues, remains elusive. Here, we utilized an antibody screening platform and machine learning prediction pipeline (InfinityFlow) to profile >200 proteins in T and T cells in solid organs and barrier locations.

The SWI/SNF chromatin remodeling complexes BAF and PBAF differentially regulate epigenetic transitions in exhausted CD8 T cells.

CD8 T cell exhaustion (Tex) limits disease control during chronic viral infections and cancer. Here, we investigated the epigenetic factors mediating major chromatin-remodeling events in Tex-cell development. A protein-domain-focused in vivo CRISPR screen identified distinct functions for two versions of the SWI/SNF chromatin-remodeling complex in Tex-cell differentiation.

Tissue-resident memory T (T ) cells: Front-line workers of the immune system.

Tissue-resident memory T (T ) cells play a vital role in local immune protection against infection and cancer. The location of T cells within peripheral tissues at sites of pathogen invasion allows for the rapid detection and elimination of microbes, making their generation an attractive goal for the development of next-generation vaccines. Here, we discuss differential requirements for CD8 T cell development across tissues with implications for establishing local prophylactic immunity, emphasizing the role of tissue-derived factors, local antigen, and adjuvants on T cell generation in the context of vaccination.

ICOS-play: dressing T cells for residency.

Efficient generation of tissue-resident memory T (T) cells is essential for long-lived immune protection in barrier tissues. Peng et al. now show that the costimulatory molecule ICOS enhances CD8 T cell lodgment by promoting early tissue retention.

Sphingosine 1-phosphate receptor 5 (S1PR5) regulates the peripheral retention of tissue-resident lymphocytes.

Tissue-resident memory T (TRM) cells provide long-lasting immune protection. One of the key events controlling TRM cell development is the local retention of TRM cell precursors coupled to downregulation of molecules necessary for tissue exit. Sphingosine-1-phosphate receptor 5 (S1PR5) is a migratory receptor with an uncharted function in T cells.

Discrete tissue microenvironments instruct diversity in resident memory T cell function and plasticity.

Tissue-resident memory T (T) cells are non-recirculating cells that exist throughout the body. Although T 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 cell heterogeneity between organs and find that the different environments in which these cells differentiate dictate T cell function, durability and malleability.

Ptpn2 and KLRG1 regulate the generation and function of tissue-resident memory CD8+ T cells in skin.

Tissue-resident memory T cells (TRM cells) are key elements of tissue immunity. Here, we investigated the role of the regulator of T cell receptor and cytokine signaling, Ptpn2, in the formation and function of TRM cells in skin. Ptpn2-deficient CD8+ T cells displayed a marked defect in generating CD69+ CD103+ TRM cells in response to herpes simplex virus type 1 (HSV-1) skin infection.

Decoding Tissue-Residency: Programming and Potential of Frontline Memory T Cells.

Memory T-cell responses are partitioned between the blood, secondary lymphoid organs, and nonlymphoid tissues. Tissue-resident memory T (Trm) cells are a population of immune cells that remain permanently in tissues without recirculating in blood. These nonrecirculating cells serve as a principal node in the anamnestic response to invading pathogens and developing malignancies.

Systemic Inflammation Suppresses Lymphoid Tissue Remodeling and B Cell Immunity during Concomitant Local Infection.

Concurrent infection with multiple pathogens occurs frequently in individuals and can result in exacerbated infections and altered immunity. However, the impact of such coinfections on immune responses remains poorly understood. Here, we reveal that systemic infection results in an inflammation-induced suppression of local immunity.

PTPN2 phosphatase deletion in T cells promotes anti-tumour immunity and CAR T-cell efficacy in solid tumours.

Although adoptive T-cell therapy has shown remarkable clinical efficacy in haematological malignancies, its success in combating solid tumours has been limited. Here, we report that PTPN2 deletion in T cells enhances cancer immunosurveillance and the efficacy of adoptively transferred tumour-specific T cells. T-cell-specific PTPN2 deficiency prevented tumours forming in aged mice heterozygous for the tumour suppressor p53.

Bhlhe40 Keeps Resident T Cells Too Fit to Quit.

Factors regulating the differentiation of tissue-resident memory T (T) cells and tumor-infiltrating lymphocytes (TILs) are incompletely understood. In this issue of Immunity, Li et al. identify Bhlhe40 as a transcriptional regulator of CD8 T cell and TIL persistence and activity by orchestrating metabolic and epigenetic programming.

Tissue-Resident Memory T Cells in Cancer Immunosurveillance.

Following their activation and expansion in response to foreign threats, many T cells are retained in peripheral tissues without recirculating in the blood. These tissue-resident CD8 memory T (T) cells patrol barrier surfaces and nonlymphoid organs, where their critical role in protecting against viral and bacterial infections is well established. Recent evidence suggests that T cells also play a vital part in preventing the development and spread of solid tumors.

Tissue-resident memory T cells orchestrate tumour-immune equilibrium.

The immune system can prevent tumour development by engaging in a process termed cancer immunosurveillance, during which immune cells such as T cells restrict tumour growth either by completely eradicating cancer cells in a process of 'elimination' or by suppressing cancer cell outgrowth by establishing a state of tumour-immune 'equilibrium'. Most cancers develop within epithelial layers of tissues but circulating T cells are largely excluded from these epithelial tissue compartments in the absence of infection or overt inflammation. In contrast, CD8 tissue-resident memory T (T) cells reside permanently within epithelial layers of peripheral tissues without recirculating in blood.

TCF-1 limits the formation of Tc17 cells via repression of the MAF-RORγt axis.

Interleukin (IL)-17-producing CD8 T (Tc17) cells have emerged as key players in host-microbiota interactions, infection, and cancer. The factors that drive their development, in contrast to interferon (IFN)-γ-producing effector CD8 T cells, are not clear. Here we demonstrate that the transcription factor TCF-1 () regulates CD8 T cell fate decisions in double-positive (DP) thymocytes through the sequential suppression of MAF and RORγt, in parallel with TCF-1-driven modulation of chromatin state.

Author Correction: Tissue-resident memory CD8 T cells promote melanoma-immune equilibrium in skin.

Panel j was inadvertently labelled as panel k in the caption to Fig. 4. Similarly, 'Fig.

Tissue-resident memory CD8 T cells promote melanoma-immune equilibrium in skin.

The immune system can suppress tumour development both by eliminating malignant cells and by preventing the outgrowth and spread of cancer cells that resist eradication. Clinical and experimental data suggest that the latter mode of control-termed cancer-immune equilibrium-can be maintained for prolonged periods of time, possibly up to several decades. Although cancers most frequently originate in epithelial layers, the nature and spatiotemporal dynamics of immune responses that maintain cancer-immune equilibrium in these tissue compartments remain unclear.

Local proliferation maintains a stable pool of tissue-resident memory T cells after antiviral recall responses.

Although tissue-resident memory T cells (T cells) are critical in fighting infection, their fate after local pathogen re-encounter is unknown. Here we found that skin T cells engaged virus-infected cells, proliferated in situ in response to local antigen encounter and did not migrate out of the epidermis, where they exclusively reside. As a consequence, secondary T cells formed from pre-existing T cells, as well as from precursors recruited from the circulation.