Too Much of a Good Thing? Tim-3 and TCR Signaling in T Cell Exhaustion

Ferris, Robert L.; Lu, Binfeng; Kane, Larry

doi:10.4049/jimmunol.1400557

Cited by 150 publications

(118 citation statements)

References 62 publications

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“…8). This hypothesis is supported by a similar model proposed by Ferris et al (11) in that engagement of TIM-3 results in signaling through mTOR resulting in either exhaustion or activation depending on the duration of signaling.…”

Section: Discussionsupporting

confidence: 73%

“…Expression of TIM-3 in Jurkat T cells enhances TCR signaling under weak stimulation but not during stronger TCR signaling (9,10). The functional outcome of TIM-3 engagement may depend on the strength of TCR activation such that optimal signaling results in a negative event, whereas TIM-3 engagement coincident with weaker TCR activation enhances T cell responses (11). This dichotomy could explain reports implicating TIM-3 in both T cell activation and exhaustion.…”

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confidence: 99%

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TIM-3 Engagement Promotes Effector Memory T Cell Differentiation of Human Antigen-Specific CD8 T Cells by Activating mTORC1

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Chornoguz

Leander

et al. 2017

The Journal of Immunology

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T cell expression of TIM-3 following Ag encounter has been associated with a continuum of functional states ranging from effector memory T cells to exhaustion. We have designed an in vitro culture system to specifically address the impact of anti–TIM-3/TIM-3 engagement on human Ag-specific CD8 T cells during a normal response to Ag and found that anti–TIM-3 treatment enhances T cell function. In our in vitro T cell culture system, MART1-specific CD8 T cells were expanded from healthy donors using artificial APCs. To ensure that the T cells were the only source of TIM-3, cells were rechallenged with peptide-loaded artificial APCs in the presence of anti–TIM-3 Ab. In these conditions, anti–TIM-3 treatment promotes generation of effector T cells as shown by acquisition of an activated phenotype, increased cytokine production, enhanced proliferation, and a transcription program associated with T cell differentiation. Activation of mTORC1 has been previously demonstrated to enhance CD8 T cell effector function and differentiation. Anti–TIM-3 drives CD8 T cell differentiation through activation of the mTORC1 as evidenced by increased levels of phosphorylated S6 protein and rhebl1 transcript. Altogether these findings suggest that anti–TIM-3, together with Ag, drives differentiation in favor of effector T cells via the activation of mTOR pathway. To our knowledge, this is the first report demonstrating that TIM-3 engagement during Ag stimulation directly influences T cell differentiation through mTORC1.

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Section: Discussionsupporting

confidence: 73%

mentioning

confidence: 99%

TIM-3 Engagement Promotes Effector Memory T Cell Differentiation of Human Antigen-Specific CD8 T Cells by Activating mTORC1

Chi-Sabins

Chornoguz

Leander

et al. 2017

The Journal of Immunology

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“…Therefore, a thorough understanding of the cognate antigens of exhausted T cells encountered during aging will be required to clarify their cytokine profile following antigen‐specific stimulation and to determine the cytotoxicity of CD8 + T cells. Additionally, the direct inhibitory role of Tim‐3 molecule has been controversial in exhausted T cells, and its role and the underlying mechanism in aging must be further elucidated (Ferris et al ., 2014). …”

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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“…27 Nonetheless, how Tim-3 mediates suppression of T cell activation or effector function is poorly understood, even though Tim-3 has been recognized as an additional marker of exhaustion on PD-1 C T cells in cancers and chronic viral infection. Recently, Tim-3 was proposed to help drive T cell exhaustion by augmenting TCR/CD28 signaling, 26,38 since excessive and constitutive TCR signaling, especially mTORC1, has been suggested to be critical for the development of T cell exhaustion. Another non-exclusive possibility is that the expression of Tim-3 observed in settings of high levels of PD-1 (including in HNSCC TIL) may represent a pro-survival mechanism in such cells.…”

Section: Discussionmentioning

confidence: 99%

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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Too Much of a Good Thing? Tim-3 and TCR Signaling in T Cell Exhaustion

Cited by 150 publications

References 62 publications

TIM-3 Engagement Promotes Effector Memory T Cell Differentiation of Human Antigen-Specific CD8 T Cells by Activating mTORC1

TIM-3 Engagement Promotes Effector Memory T Cell Differentiation of Human Antigen-Specific CD8 T Cells by Activating mTORC1

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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Too Much of a Good Thing? Tim-3 and TCR Signaling in T Cell Exhaustion

Cited by 150 publications

References 62 publications

TIM-3 Engagement Promotes Effector Memory T Cell Differentiation of Human Antigen-Specific CD8 T Cells by Activating mTORC1

TIM-3 Engagement Promotes Effector Memory T Cell Differentiation of Human Antigen-Specific CD8 T Cells by Activating mTORC1

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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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