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Tissue-resident memory T (T RM ) 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 RM cell fate remains poorly understood. Here, we show that whereas skin T RM 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 RM cells in the small intestine. We found that RA was required for the long-term maintenance of intestinal T RM populations, in part by impeding their retrograde migration. Moreover, enhanced RA signaling modulated T RM cell phenotype and function, a phenomenon mirrored in mice with increased microbial diversity. Together, our findings reveal RA as a fundamental component of the host-environment interaction that directs immunosurveillance in tissues., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Memory CD8 + T cells can be broadly divided into circulating (T CIRCM ) and tissue-resident memory T (T RM ) populations. Despite well-defined migratory and transcriptional differences, the phenotypic and functional delineation of T CIRCM and T RM 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 CIRCM and T RM cells in solid organs and barrier locations. High-dimensional analyses revealed unappreciated heterogeneity within T CIRCM and T RM cell lineages across nine different organs after either local or systemic murine infection models. Additionally, we demonstrated the relative effectiveness of strategies allowing for the selective ablation of T CIRCM or T RM populations across organs and identified CD55, KLRG1, CXCR6, and CD38 as stable markers for characterizing memory T cell function during inflammation. Together, these data and analytical framework provide an in-depth resource for memory T cell classification in both steady-state and inflammatory conditions., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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. Depletion of the canonical SWI/SNF form, BAF, impaired initial CD8 + T cell responses in acute and chronic infection. In contrast, disruption of PBAF enhanced Tex-cell proliferation and survival. Mechanistically, PBAF regulated the epigenetic and transcriptional transition from TCF-1 + progenitor Tex cells to more differentiated TCF-1 - Tex subsets. Whereas PBAF acted to preserve Tex progenitor biology, BAF was required to generate effector-like Tex cells, suggesting that the balance of these factors coordinates Tex-cell subset differentiation. Targeting PBAF improved tumor control both alone and in combination with anti-PD-L1 immunotherapy. Thus, PBAF may present a therapeutic target in cancer immunotherapy., Competing Interests: Declaration of interests E.J.W. is a member of the Parker Institute for Cancer Immunotherapy, which supports research in the Wherry laboratory. E.J.W. is an advisor for Danger Bio, Janssen, New Limit, Marengo, Pluto Immunotherapeutics Related Sciences, Santa Ana Bio, Synthekine, and Surface Oncology. E.J.W. is a founder of and holds stock in Surface Oncology, Danger Bio, and Arsenal Biosciences., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Factors regulating the differentiation of tissue-resident memory T (T RM ) 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 RM cell and TIL persistence and activity by orchestrating metabolic and epigenetic programming., (Copyright © 2019 Elsevier Inc. All rights reserved.)