Self-reactivity controls the basal metabolism and in vivo function of CD4 T cells

Relatively little is known with regard to CD4 T cell memory formation and metabolism, in part because CD4 T cell numbers remain low during a recall infection. Further, the contribution of self-peptide-MHC signaling (during both thymic T cell development and peripheral maintenance) to metabolic programming, if any, remains unknown. To address these questions, we have employed LLO-Hi5 and LLO-Lo5, two TCRtg CD4 T cells that recognize the same Listeria epitope with the same affinity. LLO-Hi5 CD4 T cells are highly self-reactive and respond poorly in a primary infection but robustly in a secondary infection. Less self-reactive LLO-Lo5 cells respond well during primary infection but poorly during secondary infection. We performed metabolic profiling to determine whether differences in response during infection were linked to metabolic differences between LLO-Lo5 and LLO-Hi5. We found that LLO-Lo5 had dramatically higher respiration and glycolytic rates relative to LLO-Hi5, and hypothesized that the decreased metabolism resulting from a strong interaction with self was mediated through TCR signaling. To test this hypothesis, we generated a knockin mouse expressing the Scn5a voltage gated sodium channel. This channel, when normally expressed in DP thymocytes, enhances TCR-mediated signaling. We found that overexpression of Scn5a in peripheral T cells increased TCR-proximal signaling. Further, Scn5a-expressing LLO-Lo5 cells displayed an impaired response during a primary infection. In this way, we demonstrate that tuning of TCR sensitivity to self can be used to alter in vivo immune responses. These studies highlight the critical relationship between TCR:self-pMHC interaction, metabolism, and the immune response to infection.