T-cell receptor signal strength and epigenetic control of Bim predict memory CD8+ T-cell fate

Li, Kun Po; Ladle, Brian H.; Kurtuluş, Sema; Sholl, Allyson; Shanmuganad, Sharmila; Hildeman, David A.

doi:10.1038/s41418-019-0410-x

Cited by 18 publications

(15 citation statements)

References 63 publications

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“…Importantly, enrichment of TCR‐related genes TRAV30 and NR4A1 (Nur77) was also detected. Nur77 is known to indicate T‐cell receptor signaling strength and is associated with memory cell development (Li et al , 2020 ; Shin et al , 2020 ). Notably, Nur77 has recently been identified as a central regulator of T‐cell immunometabolism (Liebmann et al , 2018 ).…”

Section: Resultsmentioning

confidence: 99%

Very‐low‐carbohydrate diet enhances human T‐cell immunity through immunometabolic reprogramming

et al. 2021

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Very‐low‐carbohydrate diet triggers the endogenous production of ketone bodies as alternative energy substrates. There are as yet unproven assumptions that ketone bodies positively affect human immunity. We have investigated this topic in an in vitro model using primary human T cells and in an immuno‐nutritional intervention study enrolling healthy volunteers. We show that ketone bodies profoundly impact human T‐cell responses. CD4+, CD8+, and regulatory T‐cell capacity were markedly enhanced, and T memory cell formation was augmented. RNAseq and functional metabolic analyses revealed a fundamental immunometabolic reprogramming in response to ketones favoring mitochondrial oxidative metabolism. This confers superior respiratory reserve, cellular energy supply, and reactive oxygen species signaling. Our data suggest a very‐low‐carbohydrate diet as a clinical tool to improve human T‐cell immunity. Rethinking the value of nutrition and dietary interventions in modern medicine is required.

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Section: Resultsmentioning

confidence: 99%

Very‐low‐carbohydrate diet enhances human T‐cell immunity through immunometabolic reprogramming

et al. 2021

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“…Although strong TCR stimulation is typically identified with terminal T cell differentiation ( 30 ), a recent study demonstrated that greater TCR stimulation can favor T CM differentiation when coupled to high levels of Bim and Bcl2 ( 31 ), which would not be dependent on differences in viral loads. However, it is also possible that PSGL-1-deficiency allows for greater activation of SLECs due to more limited PD-1 expression, thereby driving their terminal differentiation and promoting increased representation of MPECs.…”

Section: Discussionmentioning

confidence: 99%

PSGL-1 Is a T Cell Intrinsic Inhibitor That Regulates Effector and Memory Differentiation and Responses During Viral Infection

et al. 2021

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Effective T cell differentiation during acute virus infections leads to the generation of effector T cells that mediate viral clearance, as well as memory T cells that confer protection against subsequent reinfection. While inhibitory immune checkpoints have been shown to promote T cell dysfunction during chronic virus infections and in tumors, their roles in fine tuning the differentiation and responses of effector and memory T cells are only just beginning to be appreciated. We previously identified PSGL-1 as a fundamental regulator of T cell exhaustion that sustains expression of several inhibitory receptors, including PD-1. We now show that PSGL-1 can restrict the magnitude of effector T cell responses and memory T cell development to acute LCMV virus infection by limiting survival, sustaining PD-1 expression, and reducing effector responses. After infection, PSGL-1-deficient effector T cells accumulated to a greater extent than wild type T cells, and preferentially generated memory precursor cells that displayed enhanced accumulation and functional capacity in response to TCR stimulation as persisting memory cells. Although, PSGL-1-deficient memory cells did not exhibit inherent greater sensitivity to cell death, they failed to respond to a homologous virus challenge after adoptive transfer into naïve hosts indicating an impaired capacity to generate memory effector T cell responses in the context of viral infection. These studies underscore the function of PSGL-1 as a key negative regulator of effector and memory T cell differentiation and suggest that PSGL-1 may limit excessive stimulation of memory T cells during acute viral infection.

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“…However, another consideration is the speculated roles of EZH2 in TCR signaling supported by evidence of non-nuclear localization ( 57 , 58 ). Although seemingly disparate, EZH2's proposed cytoplasmic involvement in TCR signaling could very well explain the differences in CD8+ T cell differentiation as TCR signal strength is known to influence memory versus effector cell fate ( 46 , 59 ). In the context of cancer, there is chronic antigen stimulation where such phenotypes as SLEC and MPEC may no longer be applicable, making the comparison to acute pathogenic infection more complicated in defining the CD8+ T cell subpopulations affected by EZH2 inhibition.…”

Section: Discussionmentioning

confidence: 99%

EZH2 as a Regulator of CD8+ T Cell Fate and Function

2020

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Enhancer of zeste 2 (EZH2) is the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2) that mediates di-and trimethylation of histone 3 lysine 27 effectively precluding successful gene transcription at these loci. This class of epigenetic modifications facilitates the maintenance of tissue-specific cellular transcriptional programs as cells undergoing successive rounds of proliferation. CD8+ T cells are effective mediators of adaptive immunity and function to eliminate virus-and bacteria-infected cells as well as tumor cells. Upon recognition of cognate antigen, T cells undergo activation/proliferation to clear the target cells. The heterogeneous population of responding T cells formed during these proliferative events thus rely on epigenetic modifications to ensure identity and confer functional capabilities. In this review, we will focus on the role of the dynamic expression EZH2 in shaping the epigenetic landscape of CD8+ T cell fate and function, with a particular emphasis on infection and cancer. We also explore competing hypotheses pertaining to EZH2 function and the prospects of clinical EZH2 inhibitors in fine-tuning T cell responses.

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T-cell receptor signal strength and epigenetic control of Bim predict memory CD8+ T-cell fate

Cited by 18 publications

References 63 publications

Very‐low‐carbohydrate diet enhances human T‐cell immunity through immunometabolic reprogramming

Very‐low‐carbohydrate diet enhances human T‐cell immunity through immunometabolic reprogramming

PSGL-1 Is a T Cell Intrinsic Inhibitor That Regulates Effector and Memory Differentiation and Responses During Viral Infection

EZH2 as a Regulator of CD8+ T Cell Fate and Function

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