Tonic TCR Signaling Inversely Regulates the Basal Metabolism of CD4+ T Cells

Abstract

The contribution of self-peptide-MHC signaling in CD4 + T cells to metabolic programming has not been definitively established. In this study, we employed LLO118 and LLO56, two TCRtg CD4 + T cells that recognize the same Listeria epitope. We previously have shown that LLO56 T cells are highly self-reactive and respond poorly in a primary infection, whereas LLO118 cells, which are less selfreactive, respond well during primary infection. We performed metabolic profiling and found that naive LLO118 had a dramatically higher basal respiration rate, a higher maximal respiration rate, and a higher glycolytic rate relative to LLO56. The LLO118 cells also exhibited a greater uptake of 2-NBD-glucose, in vitro and in vivo. We extended the correlation of low self-reactivity (CD5 lo) with high basal metabolism using two other CD4 + TCRtg cells with known differences in self-reactivity, AND and Marilyn. We hypothesized that the decreased metabolism resulting from a strong interaction with self was mediated through TCR signaling. We then used an inducible knock-in mouse expressing the Scn5a voltage-gated sodium channel. This channel, when expressed in peripheral T cells, enhanced basal TCR-mediated signaling, resulting in decreased respiration and glycolysis, supporting our hypothesis. Genes and metabolites analysis of LLO118 and LLO56 T cells revealed significant differences in their metabolic pathways, including the glycerol phosphate shuttle. Inhibition of this pathway reverts the metabolic state of the LLO118 cells to be more LLO56 like. Overall, these studies highlight the critical relationship between peripheral TCR-self-pMHC interaction, metabolism, and the immune response to infection. ImmunoHorizons, 2020, 4: 485-497.

Strength of tonic T cell receptor signaling instructs T follicular helper cell–fate decisions

“…After positive selection, mature CD4 + T cells exit the thymus and circulate in the periphery where they survey pMHC, which, in the absence of an immune challenge, will be occupied by self-peptide. Tonic signaling does not propagate canonical T cell activation; yet, these weaker TCR interactions still affect basal signaling, gene expression, and metabolic activity 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 . Multiple markers (including CD5 24 and Nur77 25 , 26 ) have informed us of a broad spectrum of tonic signaling strengths experienced by the diverse repertoire of TCRs in a polyclonal population, and recent work suggests tonic signaling may be responsible for discretely tuning individual CD4 + T cell responses to foreign antigen 15 , 27 , 28 .…”

Direct tissue sensing reprograms TLR4+Tfh-like cells inflammatory profile in the joints of rheumatoid arthritis patients

“…Recognition of noncognate-antigen:HLA-DR complexes on APCs by the TCR, albeit incapable of driving full T cell activation, generates nuanced effects on T cell activation and gene expression 40, 41 . We posited that homotypic T-T cell interactions through non-cognate HLA-DR:TCR contacts could control TLR4 expression on T cells.…”

“…We have broadened the range of molecules involved in homotypic T:T cell interactions by identifying that they can be additionally established through non-cognate HLA-DR:TCR interactions. Non-cognate HLA-DR:TCR interactions between APCs and T cells are known to alter T cell genetic profile 40, 41 . Thus, it is possible that homotypic T-T cell interactions through non-cognate HLA-DR:TCR contacts might drive TLR4 gene expression.…”

Divide and Conquer: Phenotypic and Temporal Heterogeneity Within CD8+ T Cell Responses

“…Investigations into the mechanism behind this enhanced proliferation revealed greater responsiveness to inflammatory cues but not enhanced antigenic pMHC binding (142). Further associations of tonic signaling and CD5 expression have been found with other features involved in T cell responsiveness, including expression of the phosphatases CD45 and PTPN2 (143,144) and metabolic state (145). Moreover, a study in naïve CD4 + T cells demonstrated CD5associated differences in chromatin accessibility (146), suggesting that self-pMHC signaling can cause long-lived reprogramming in naïve T cells.…”