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Accumulation of TCR signaling from self-antigens in naive CD8 T cells mitigates early responsiveness.

ABSTRACT: The cumulative effects of T cell receptor (TCR) signal transduction over extended periods of time influences T cell biology, such as the positive selection of immature thymocytes or the proliferative responses of naive T cells. Naive T cells experience recurrent TCR signaling in response to self-antigens in the steady state. However, how these signals influence the responsiveness of naive CD8⁺ T cells to subsequent agonist TCR stimulation remains incompletely understood. We investigated how naive CD8⁺ T cells that experienced relatively low or high levels of TCR signaling in response to self-antigens respond to stimulation with foreign antigens. A transcriptional reporter of Nr4a1 (Nur77-GFP) revealed substantial heterogeneity of the amount of TCR signaling naive CD8⁺ T cells accumulate in the steady state. Nur77-GFP^HI cells exhibited diminished T cell activation and secretion of IFNγ and IL-2 relative to Nur77-GFP^LO cells in response to agonist TCR stimulation. Differential gene expression analyses revealed upregulation of genes associated with acutely stimulated T cells in Nur77-GFP^HI cells but also increased expression of negative regulators such as the phosphatase Sts1. Responsiveness of Nur77-GFP^HI cells to TCR stimulation was partially restored at the level of IFNγ secretion by deficiency of Sts1 or the ubiquitin ligase Cbl-b. Our data suggest that extensive accumulation of TCR signaling during steady state conditions induces a recalibration of the responsiveness of naive CD8⁺ T cells through gene expression changes and negative regulation, at least in part, dependent on Sts1 and Cbl-b. This cell-intrinsic negative feedback loop may allow the immune system to limit the autoreactive potential of highly self-reactive naive CD8⁺ T cells.

SUBMITTER: Eggert J

PROVIDER: S-EPMC9900884 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Accumulation of TCR signaling from self-antigens in naive CD8 T cells mitigates early responsiveness.

Eggert Joel J Zinzow-Kramer Wendy M WM Hu Yuesong Y Tsai Yuan-Li YL Weiss Arthur A Salaita Khalid K Scharer Christopher D CD Au-Yeung Byron B BB

bioRxiv : the preprint server for biology 20230128

The cumulative effects of T cell receptor (TCR) signal transduction over extended periods of time influences T cell biology, such as the positive selection of immature thymocytes or the proliferative responses of naive T cells. Naive T cells experience recurrent TCR signaling in response to self-antigens in the steady state. However, how these signals influence the responsiveness of naive CD8<sup>+</sup> T cells to subsequent agonist TCR stimulation remains incompletely understood. We investigat ...[more]

PMID: 36747815

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Project description:BackgroundAffinity-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.MethodsThe 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.ResultsWe 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 μM). Similar findings were made when affinity-increased HLA-A2neg CD8 T cells were chronically exposed to HLA-A2pos-expressing target cells.ConclusionsOur 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.

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Accumulation of TCR signaling from self-antigens in naive CD8 T cells mitigates early responsiveness.

Publications

Accumulation of TCR signaling from self-antigens in naive CD8 T cells mitigates early responsiveness.

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