Mitochondria regulate adaptive immunity

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Abstract T cells are major mediators of adaptive immune responses and resolution. Previously, we found that activated T cells also increase their rate of mitochondrial oxygen consumption; and that in the absence of a critical subunit of complex III within the electron transport chain, T cells failed to be activated in vitro or in vivo. Further, we found that upon T regulatory cell (Treg cell) specific inactivation of complex III, Treg cells survived, proliferated, and maintained stable Foxp3 expression but failed to function, resulting in a scurfy-like phenotype. Our findings identified mitochondria as necessary regulators of essential conventional and regulatory T cell functions. A central question based on our previous observations is how mitochondrial metabolism controls both conventional T cell and regulatory T cell function. We propose that mitochondrial metabolism is necessary for adaptive immune functions through the generation of ETC dependent reactive oxygen species (ROS) and production of TCA cycle metabolites to control transcription factors and chromatin/DNA modifications, respectively. Mitochondrial ETC complex I and III are the dominant sites of ROS generation. TCA cycle enzymes can elevate the production of succinate and L-2-hydroxygluatrate (L-2HG) to control DNA and histone methylation. Thus, we hypothesize that conventional CD8T cells require mitochondrial ROS for activation and memory differentiation; but that maintenance of memory CD8 T cells requires TCA cycle metabolites. Also, we postulate that mitochondrial TCA cycle metabolites control Treg suppressive function by controlling DNA methylation. To test this hypothesis, we propose the following aims: Specific Aim I: Determine whether complex I or III generated ROS are required for CD8 T cell activation, and memory formation while TCA cycle metabolites are essential for memory maintenance. Specific Aim II: Determine whether TCA cycle metabolites control Treg cell suppressive function. Together these aims will define the mechanisms by which mitochondria dictate T cell fate and function. 1