Dataset Information

TCR Dependent Metabolic Programming Regulates Autocrine IL-4 Production Resulting in Self-Tuning of the CD8+ T Cell Activation Setpoint.

ABSTRACT: The ability of T cells to sense and respond to environmental cues by altering their functional capabilities is critical for a safe and optimally protective immune response. One of the important properties that contributes to this goal is the activation set-point of the T cell. Here we report a new pathway through which TCR transgenic OT-I CD8+ T cells can self-tune their activation threshold. We find that in the presence of a strong TCR engagement event there is a shift in the metabolic programming of the cell where both glycolysis and oxidative phosphorylation are significantly increased. This diverges from the switch to a predominantly glycolytic profile that would be predicted following naïve T cell activation. Our data suggest this altered metabolic program results in the production of autocrine IL-4. Both metabolic pathways are required for this cytokine to be made. IL-4 signaling in the activated OT-I CD8+ T cell results in modulation of the sensitivity of the cell, establishing a higher activation setpoint that is maintained over time. Together these data demonstrate a novel mechanism for the regulation of IL-4 production in CD8+ T cells. Further, they reveal a new pathway for the self-tuning of peptide sensitivity. Finally, these studies uncover an unexpected role for oxidative phosphorylation in regulating differentiation in these cells.

SUBMITTER: Crofts KF

PROVIDER: S-EPMC7145404 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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TCR Dependent Metabolic Programming Regulates Autocrine IL-4 Production Resulting in Self-Tuning of the CD8<sup>+</sup> T Cell Activation Setpoint.

Crofts Kali F KF Holbrook Beth C BC Soto-Pantoja David R DR Ornelles David A DA Alexander-Miller Martha A MA

Frontiers in immunology 20200331

The ability of T cells to sense and respond to environmental cues by altering their functional capabilities is critical for a safe and optimally protective immune response. One of the important properties that contributes to this goal is the activation set-point of the T cell. Here we report a new pathway through which TCR transgenic OT-I CD8<sup>+</sup> T cells can self-tune their activation threshold. We find that in the presence of a strong TCR engagement event there is a shift in the metabol ...[more]

PMID: 32300344

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Project description:BACKGROUND:Affinity-optimized T cell receptor (TCR)-engineered lymphocytes targeting tumor antigens can mediate potent antitumor responses in cancer patients, but also bear substantial risks for off-target toxicities. Most preclinical studies have focused on T cell responses to antigen-specific stimulation. In contrast, little is known on the regulation of T cell responsiveness through continuous TCR triggering and consequent tonic signaling. Here, we addressed the question whether increasing the TCR affinity can lead to chronic interactions occurring directly between TCRs and MHC-(self) molecules, which may modulate the overall functional potency of tumor-redirected CD8 T cells. For this purpose, we developed two complementary human CD8 T cell models (i.e. HLA-A2 knock-in and knock-out) engineered with incremental-affinity TCRs to the HLA-A2/NY-ESO-1 tumor antigen. METHODS:The impact of HLA-A2 recognition, depending on TCR affinity, was assessed at the levels of the TCR/CD3 complex, regulatory receptors, and signaling, under steady-state conditions and in kinetic studies. The quality of CD8 T cell responses was further evaluated by gene expression and multiplex cytokine profiling, as well as real-time quantitative cell killing, combined with co-culture assays. RESULTS:We found that HLA-A2 per se (in absence of cognate peptide) can trigger chronic activation followed by a tolerance-like state of tumor-redirected CD8 T cells with increased-affinity TCRs. HLA-A2pos but not HLA-A2neg T cells displayed an activation phenotype, associated with enhanced upregulation of c-CBL and multiple inhibitory receptors. T cell activation preceded TCR/CD3 downmodulation, impaired TCR signaling and functional hyporesponsiveness. This stepwise activation-to-hyporesponsive state was dependent on TCR affinity and already detectable at the upper end of the physiological affinity range (KD???1??M). Similar findings were made when affinity-increased HLA-A2neg CD8 T cells were chronically exposed to HLA-A2pos-expressing target cells. CONCLUSIONS:Our observations indicate that sustained interactions between affinity-increased TCR and self-MHC can directly adjust the functional potential of T cells, even in the absence of antigen-specific stimulation. The observed tolerance-like state depends on TCR affinity and has therefore potential implications for the design of affinity-improved TCRs for adoptive T cell therapy, as several engineered TCRs currently used in clinical trials share similar affinity properties.

Dataset Information

TCR Dependent Metabolic Programming Regulates Autocrine IL-4 Production Resulting in Self-Tuning of the CD8+ T Cell Activation Setpoint.

Publications

TCR Dependent Metabolic Programming Regulates Autocrine IL-4 Production Resulting in Self-Tuning of the CD8<sup>+</sup> T Cell Activation Setpoint.

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