Progenitor and Terminal Subsets of CD8
            <sup>+</sup>
            T Cells Cooperate to Contain Chronic Viral Infection

Paley, Michael; Kroy, Daniela C.; Odorizzi, Pamela M.; Johnnidis, Jonathan B.; Dolfi, Douglas V.; Barnett, Burton E.; Bikoff, Elizabeth K.; Robertson, Elizabeth J.; Lauer, Georg M.; Reiner, Steven L.; Wherry, E. John

doi:10.1126/science.1229620

Cited by 779 publications

(1,056 citation statements)

References 41 publications

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“…Such a replacement seems to occur in CMV infections 55 . A precursor progeny relation between subpopulations of T-cells that differ in expressing Tbox transcription factors has also been shown in LCMV clone-13 infected mice 72 .…”

Section: Why Are Memory-like Cells Formed In Chronic Infections?mentioning

confidence: 69%

T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?

et al. 2014

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Chronic viral infections and malignant tumours induce T cells that have a reduced ability to secrete effector cytokines and have upregulated expression of the inhibitory receptor PD1 (programmed cell death protein 1). These features have so far been considered to mark terminally differentiated 'exhausted' T cells. However, several recent clinical and experimental observations indicate that phenotypically exhausted T cells can still mediate a crucial level of pathogen or tumour control. In this Opinion article, we propose that the exhausted phenotype results from a differentiation process in which T cells stably adjust their effector capacity to the needs of chronic infection. We argue that this phenotype is optimized to cause minimal tissue damage while still mediating a critical level of pathogen control. In contrast to the presently held view of functional exhaustion, this new concept better reflects the pathophysiology and clinical manifestations of persisting infections, and it provides a rationale for emerging therapies that enhance T cell activity in chronic infection and cancer by blocking inhibitory receptors. Daniel T. Utzschneider Division of Immunology and Allergy of the Lausanne University Hospital (CHUV) and Swiss Vaccine Research Institute (SVRI), Lausanne, SwitzerlandDaniel Utzschneider is a PhD student of Dietmar Zehn. His research is focused on T-cell differentiation in chronic infection. Susanne G. Oberle Division of Immunology and Allergy of the Lausanne University Hospital (CHUV) and Swiss Vaccine Research Institute (SVRI), Lausanne, SwitzerlandSusanne Oberle is a PhD student of Dietmar Zehn. Her research interests are focused on investigating T-cell responses in acute and chronic infections. and it provides a rational for emerging therapies that enhance T-cell activity in chronic infection and cancer by blocking inhibitory receptors. Christian Münz PhD

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Section: Why Are Memory-like Cells Formed In Chronic Infections?mentioning

confidence: 69%

T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?

et al. 2014

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“…Interestingly, Tim‐3‐expressing CD8 + T cells retained an ability to produce IFN‐γ similar to other subsets upon stimulation of PMA and ionomycin, and even expressed more mRNA than Tim‐3 − PD‐1 − CD8 + T cells, whereas their expression of TNF‐α was significantly reduced. In agreement with findings regarding exhausted T cells in chronic infection, we also found that aged PD‐1 expressing CD8 + T cells showed T‐bet lo and Eomesodermin (Eomes) hi expression (Paley et al ., 2012) (Fig. 6D).…”

Section: Resultsmentioning

confidence: 94%

“…6D). Because the expression of Eomes has been found to increase in the terminal progeny of exhausted T cells, it seems that Tim‐3 + PD‐1 + cells among aged CD8 + T cells are most similar to the terminal progeny (Paley et al ., 2012). Eomes may function instead of T‐bet to express IFN‐γ in those cells; however, this must be elucidated in future studies.…”

Section: Discussionmentioning

confidence: 99%

Characterization of age‐associated exhausted CD8⁺ T cells defined by increased expression of Tim‐3 and PD‐1

et al. 2016

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SummaryAging is accompanied by altered T‐cell responses that result in susceptibility to various diseases. Previous findings on the increased expression of inhibitory receptors, such as programmed cell death protein 1 (PD‐1), in the T cells of aged mice emphasize the importance of investigations into the relationship between T‐cell exhaustion and aging‐associated immune dysfunction. In this study, we demonstrate that T‐cell immunoglobulin mucin domain‐3 (Tim‐3), another exhaustion marker, is up‐regulated on aged T cells, especially CD8+ T cells. Tim‐3‐expressing cells also produced PD‐1, but Tim‐3+ PD‐1+ CD8+ T cells had a distinct phenotype that included the expression of CD44 and CD62L, from Tim‐3− PD‐1+ cells. Tim‐3+ PD‐1+ CD8+ T cells showed more evident properties associated with exhaustion than Tim‐3− PD‐1+ CD8+ T cells: an exhaustion‐related marker expression profile, proliferative defects following homeostatic or TCR stimulation, and altered production of cytokines. Interestingly, these cells produced a high level of IL‐10 and induced normal CD8+ T cells to produce IL‐10, which might contribute to immune dysregulation in aged mice. The generation of Tim‐3‐expressing CD8+ T cells in aged mice seems to be mediated by encounters with antigens but not by specific infection, based on their high expression of CD49d and their unbiased TCR Vβ usage. In conclusion, we found that a CD8+ T‐cell population with age‐associated exhaustion was distinguishable by its expression of Tim‐3. These results provide clues for understanding the alterations that occur in T‐cell populations with age and for improving dysfunctions related to the aging of the immune system.

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“…Interestingly, PD-1 hi Tim-3 ¡ and PD-1 C Tim-3 C CD8 C TIL had higher levels of transcripts for Blimp-1 (encoded by PRDM1) and BATF, transcription factors previously shown to impair T cell proliferation and cytokine secretion and thereby foster T cell exhaustion. 23,24 Moreover, higher expression of Eomes, which is associated with exhausted terminal progeny T cells, and lower levels of T-bet, a marker of robust and functional progenitors, 25 were observed primarily in PD-1 hi Tim-3 ¡ and PD-1 C Tim-3 C CD8 C TIL ( Fig. 2A).…”

Section: Definition Of Hnscc Til By Expression Of Pd-1 and Tim-3mentioning

confidence: 96%

Tumor-infiltrating Tim-3⁺ T cells proliferate avidly except when PD-1 is co-expressed: Evidence for intracellular cross talk

Shayan

Avery

et al. 2016

OncoImmunology

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Programmed Death 1 (PD-1) and T cell Ig and mucin domain-3 protein (Tim-3) are immune checkpoint receptors highly expressed on tumor infiltrating T lymphocytes (TIL). PD-1 inhibits T cell activation and type-1 T cell responses, while Tim-3 is proposed to mark more extensively exhausted cells, although the mechanisms underlying Tim-3 function are not clear. Trials of anti-PD-1 therapy have identified a large subset of non-responder patients, likely due to expression of alternative checkpoint molecules like Tim-3. We investigated the phenotypic and functional characteristics of T cells with differential expression of PD-1 (high/low) and Tim-3 (positive/negative), using TIL directly isolated from head and neck squamous cell carcinomas (HNSCC). Unexpectedly, we found that expression of Tim-3 alone does not necessarily mark TIL as dysfunctional/exhausted. In Tim-3-TIL, PD-1 levels correlate with T cell dysfunction, with a PD-1 low/intermed phenotype identifying recently activated and still functional cells, whereas PD-1 hi Tim-3 ¡ T cells are actually exhausted. Nonetheless, PD-1 intermed cells are still potently suppressed by PD-L1. PD-1 expression was associated with reduced phosphorylation of ribosomal protein S6 (pS6), whereas Tim-3 expression was associated with increased pS6. Using a novel mouse model for inducible Tim-3 expression, we confirmed that expression of Tim-3 does not necessarily render T cells refractory to further activation. These results suggest the existence of PD-1 and Tim-3 crosstalk in regulating antitumor T cell responses, with important implications for anti-PD-1 immunotherapy.

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Progenitor and Terminal Subsets of CD8 ⁺ T Cells Cooperate to Contain Chronic Viral Infection

Cited by 779 publications

References 41 publications

T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?

T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?

Characterization of age‐associated exhausted CD8⁺ T cells defined by increased expression of Tim‐3 and PD‐1

Tumor-infiltrating Tim-3⁺ T cells proliferate avidly except when PD-1 is co-expressed: Evidence for intracellular cross talk

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Progenitor and Terminal Subsets of CD8 + T Cells Cooperate to Contain Chronic Viral Infection

Cited by 779 publications

References 41 publications

T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?

T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?

Characterization of age‐associated exhausted CD8+ T cells defined by increased expression of Tim‐3 and PD‐1

Tumor-infiltrating Tim-3+ T cells proliferate avidly except when PD-1 is co-expressed: Evidence for intracellular cross talk

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Progenitor and Terminal Subsets of CD8 ⁺ T Cells Cooperate to Contain Chronic Viral Infection

Characterization of age‐associated exhausted CD8⁺ T cells defined by increased expression of Tim‐3 and PD‐1

Tumor-infiltrating Tim-3⁺ T cells proliferate avidly except when PD-1 is co-expressed: Evidence for intracellular cross talk