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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]

Persistent antigenic stimulation results in loss of effector function or physical deletion of antigen-specific CD8 T cells. This T-cell state is called T-cell exhaustion and occurs during chronic infection and cancer. Antigen-specific CD8 T cells during T-cell exhaustion express the inhibitory receptor PD-1, the expression of which plays a major role in T-cell dysfunction. PD-1 blockade re-invigorates CD8 T-cell immunity and has been proven effective against many different types of human cancer. To further improve the efficacy of PD-1-targeted immunotherapy in cancer patients, a better understanding of T-cell exhaustion is required. Recent studies have revealed that antigen-specific CD8 T cells during T-cell exhaustion are heterogeneous and have also uncovered the detailed mechanisms for PD-1-targeted immunotherapy. Here, we review the CD8 T-cell subsets that arise during T-cell exhaustion, the lineage relationship among these individual subsets and the role of each subset in PD-1 blockade. Also, we discuss potential strategies to enhance the efficacy of PD-1-targeted immunotherapy. [ABSTRACT FROM AUTHOR]

The article presents case study of 86-year-old Japanese woman who had history of discomfort on the chest and discusses how physical examination revealed subcutaneous nodule which without pain on the left side of the chest. It mentions how skin biopsy specimen from the left chest demonstrated the diffuse infiltration of large, atypical cells from the middle dermis to the subcutaneous fat tissue. It also mentions there was no link between pathogenesis of B-cell lymphoma and mutations..

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 CD45RBhi and CD45RBlo populations. Relative to CD45RBlo memory T cells, CD45RBhi memory T cells have lower affinity and display greater clonal diversity, as well as a persistent CD27hi phenotype. The CD45RBhi memory population displays a homeostatic survival advantage in vivo relative to CD45RBlo memory, and long-lived high-affinity cells that persisted long term convert from CD45RBlo to CD45RBhi. Human CD45RO+ memory is comprised of both CD45RBhi and CD45RBlo populations with distinct phenotypes, and antigen-specific memory to two viruses is predominantly CD45RBhi. 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. • Viral-specific CD8+ T cell memory contains both CD45RBhi and CD45RBlo populations • Low-affinity CD8+ T cell memory is CD45RBhi and possesses a CD27hiCD62Lhi phenotype • CD45RBhi CD8+ T cell memory survive better than high-affinity CD45RBlo memory in vivo • Human CD45RBhi and CD45RBlo CD8+ T cell memory populations have distinct phenotypes Krummey et al. show that viral CD8+ T cell memory has heterogeneous CD45 isoform expression. Low-affinity CD8+ T cells have high CD45RB expression and a CD27hiCD62Lhi phenotype relative to high-affinity CD45RBlo CD8+ T cells, which possess an effector-like phenotype. CD45RBhi cells survive better under homeostatic conditions in vivo. [ABSTRACT FROM AUTHOR]