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T cell exhaustion is a state of T cell dysfunction associated with expression of programmed death 1 (PD-1). Exhausted [CD8.sup.+] T cells are maintained by self-renewing stem-like T cells that provide differentiated [TIM3.sup.+] cells, a part of which possesses effector-like properties. PD-1-targeted therapies enhance T cell response by promoting differentiation of stem- like T cells toward [TIM3.sup.+] cells, but the role of mTOR during T cell exhaustion remains elusive. Here, we showed that mTOR inhibition has distinct outcomes during the beginning of and after the establishment of chronic viral infection. Blocking mTOR during the T cell expansion phase enhanced the T cell response by causing accumulation of stem-like T cells, leading to improved efficacy of PD-1 immunotherapy; whereas, after exhaustion progressed, mTOR inhibition caused immunosuppression, characterized by decreased [TIM3.sup.+] cells and increased viral load with minimal changes in stem-like T cells. Mechanistically, a cell- intrinsic mTOR signal was vital for differentiation of stem-like T cells into the [TIM3.sup.+] state in the early and late phases of chronic infection as well as during PD-1 immunotherapy. Thus, PD-1 blockade worked after cessation of mTOR inhibition, but simultaneous treatment failed to induce functional [TIM3.sup.+] cells, reducing efficacy of PD-1 immunotherapy. Our data demonstrate that mTOR regulates T cell exhaustion and have important implications for combination cancer therapies with PD-1 blockade., Introduction T cell exhaustion is a state of T cell dysfunction; it is characterized by poor effector function, impaired proliferative capacity, and expression of multiple inhibitory receptors, most notably programmed [...]

PD-1+TCF-1+ stem-like CD8 T cells act as critical resource cells for maintaining T cell immunity in chronic viral infections and cancer. In addition, they provide the proliferative burst of effector CD8 T cells after programmed death protein 1 (PD-1)–directed immunotherapy. However, it is not known whether checkpoint blockade diminishes the number of these stem-like progenitor cells as effector cell differentiation increases. To investigate this, we used the mouse model of chronic lymphocytic choriomeningitis virus (LCMV) infection. Treatment of chronically infected mice with either αPD-1 or αPD-L1 antibody not only increased effector cell differentiation from the virus-specific stem-like CD8 T cells but also increased their proliferation so their numbers were maintained. The increased self-renewal of LCMV-specific stem-like CD8 T cells was mTOR dependent. We used microscopy to understand the division of these progenitor cells and found that after PD-1 blockade, an individual dividing cell could give rise to a differentiated TCF-1− daughter cell alongside a self-renewing TCF-1+ sister cell. This asymmetric division helped to preserve the number of stem-like cells. Moreover, we found that the PD-1+TCF-1+ stem-like CD8 T cells retained their transcriptional program and their in vivo functionality in terms of responding to viral infection and to repeat PD-1 blockade. Together, our results demonstrate that PD-1 blockade does not deplete the stem-like population despite increasing effector differentiation. These findings have implications for PD-1–directed immunotherapy in humans. Editor's summary: Stem-like CD8 T cells develop during periods of persistent antigen exposure. During chronic infection and cancer, therapies can stimulate their differentiation into antigen-specific cells with effector function; yet factors controlling the integrity of the stem-like T cell pool were unknown. Studying chronic viral infection in mice, Humblin et al. found that the co-stimulatory molecule CD28 regulated metabolism of stem-like CD8 T cells expressing the inhibitory receptor PD-1 to promote self-renewal and differentiation. In companion work, Gill et al. found that PD-1 blockade, while promoting effector cell differentiation, likewise stimulated the self-renewal of these stem-like CD8 T cells, maintaining the size and functionality of the progenitor pool. Thus, immune checkpoint therapies may rejuvenate immune responses without diminishing the durability of the stem-like CD8 T cells that respond to treatment. —Sarah H. Ross [ABSTRACT FROM AUTHOR]

The identity of CD45 isoforms on the T cell surface changes following the activation of naive T cells and impacts intracellular signaling. In this study, we find that the anti-viral memory CD8 + T pool is unexpectedly comprised of both CD45RB hi and CD45RB lo populations. Relative to CD45RB lo memory T cells, CD45RB hi memory T cells have lower affinity and display greater clonal diversity, as well as a persistent CD27 hi phenotype. The CD45RB hi memory population displays a homeostatic survival advantage in vivo relative to CD45RB lo memory, and long-lived high-affinity cells that persisted long term convert from CD45RB lo to CD45RB hi . Human CD45RO + memory is comprised of both CD45RB hi and CD45RB lo populations with distinct phenotypes, and antigen-specific memory to two viruses is predominantly CD45RB hi . These data demonstrate that CD45RB status is distinct from the conventional central/effector T cell memory classification and has potential utility for monitoring and characterizing pathogen-specific CD8 + T cell responses., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)