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Antigen-specific CD8 + T cells in chronic viral infections and tumors functionally deteriorate, a process known as exhaustion. Exhausted T cells are sustained by precursors of exhausted (Tpex) cells that self-renew while continuously generating exhausted effector (Tex) cells. However, it remains unknown how Tpex cells maintain their functionality. Here, we demonstrate that Tpex cells sustained mitochondrial fitness, including high spare respiratory capacity, while Tex cells deteriorated metabolically over time. Tpex cells showed early suppression of mTOR kinase signaling but retained the ability to activate this pathway in response to antigen receptor signals. Early transient mTOR inhibition improved long-term T cell responses and checkpoint inhibition. Transforming growth factor-β repressed mTOR signaling in exhausted T cells and was a critical determinant of Tpex cell metabolism and function. Overall, we demonstrate that the preservation of cellular metabolism allows Tpex cells to retain long-term functionality to sustain T cell responses during chronic infection., Competing Interests: Declaration of interests F.S.-F.-G. has a funded research collaborative agreement with Miltenyi Biotec Australia and is a consultant for Biotheus. N.D.H. is founder and shareholder of oNKo-Innate Pty Ltd. The authors declare no other competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Following antigen-driven expansion in lymph node, transforming growth factor-β (TGFβ) is required for differentiation of skin-recruited CD8 + T cell effectors into epidermal resident memory T (Trm) cells and their epidermal persistence. We found that the source of TGFβ -supporting Trm cells was autocrine. In addition, antigen-specific Trm cells that encountered cognate antigen in the skin, and bystander Trm cells that did not, both displayed long-term persistence in the epidermis under steady-state conditions. However, when the active-TGFβ was limited or when new T cell clones were recruited into the epidermis, antigen-specific Trm cells were more efficiently retained than bystander Trm cells. Genetically enforced TGFβR signaling allowed bystander Trm cells to persist in the epidermis as efficiently as antigen-specific Trm cells in both contexts. Thus, competition between T cells for active TGFβ represents an unappreciated selective pressure that promotes the accumulation and persistence of antigen-specific Trm cells in the epidermal niche., Competing Interests: Declaration of Interests D.W.G. is a consultant and equity holder of Indalo Therapeutics, which provided compound CWHM-12. All other authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Regulated activation of the cytokine TGF-β by integrins α v β 6 and α v β 8 expressed on keratinocytes is required for residence of epidermal-resident memory T cells, but whether skin-derived signals also affect recirculating memory cells in the skin remains unclear. Here, we show that after resolution of skin vaccinia virus (VV) infection, antigen-specific circulating memory CD8 + T cells migrated into skin. In mice lacking α v β 6 and α v β 8 integrins (Itgb6 -/- Itgb8 fl/fl -K14-cre), the absence of epidermal-activated TGF-β resulted in a gradual loss of E- or P-selectin-binding central and peripheral memory populations, which were rescued when skin entry was inhibited. Skin recirculating memory cells were required for optimal host defense against skin VV infection. These data demonstrate that skin migration can persist after resolution of local skin infection and that the cytokine environment within this nonlymphoid tissue shapes the differentiation state and persistence of the central and peripheral memory-T-cell pool., (Copyright © 2019 Elsevier Inc. All rights reserved.)