A TCF1:Glucocorticoid regulatory circuit controls IL-23-driven Th17 pathogenicity

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PROJECT SUMMARY CD4+ IL-17-producing T helper cells (Th17) are known drivers of central nervous system (CNS) autoimmune inflammation in multiple sclerosis (MS), yet not all Th17 cells drive disease. Indeed, two major Th17 subtypes have been described in both mice and humans: homeostatic or non-pathogenic (npTh17) that maintain the steady state in tissue and inflammatory or pathogenic Th17 (pTh17) that drive destructive tissue inflammation. Importantly, npTh17 are precursors of pTh17 and IL-23 is known to be the switch factor for conversion of npTh17 to pTh17. However, the mechanisms by which IL-23 drives this conversion are not well understood. Identifying these mechanisms will provide critical insight for the development of novel therapeutic interventions for MS. Genetic variants in TCF7, the gene encoding the transcription factor TCF-1, have been associated with disease susceptibility in MS in genome-wide association studies, but the underlying mechanisms remain unknown. Notably, TCF-1 has been implicated in Th17 biology, but its role remains unclear due to conflicting data generated in models that have either defective T cell development or that study TCF-1 indirectly. Using mice that conditionally delete Tcf7 only in mature T cells, and thus have normal T cell development, we have found that TCF-1-deficient Th17 cells may not require IL-23R signaling for acquiring pathogenic potential. Indeed, we have found that TCF-1 is differentially regulated in npTh17 and pTh17 in vivo and that IL-23 shuts down TCF-1 expression. Our preliminary data further uncover a putative regulatory circuit that links IL-23, TCF-1, and endogenous glucocorticoid (GC) signaling. We have found that npTh17 are steroidogenic. They can produce GCs, which in turn, sustain TCF-1 expression, oppose IL23R signaling, and restrain Th17 pathogenicity. In contrast, IL-23 shuts down steroidogenesis in npTh17 cells. Accordingly, we hypothesize that a TCF-1- glucocorticoid regulatory circuit determines IL-23-driven pathogenicity in Th17 cells. We have generated several novel conditional knock-out mice with which we can study the role of TCF-1, the glucocorticoid receptor (GR), and cell-intrinsic steroidogenesis specifically in mature T cells. We will use these tools to mechanistically dissect this novel regulatory circuit. We propose the following aims: 1) Define the role of TCF-1 in opposing IL- 23-driven Th17 pathogenicity; 2) Determine how glucocorticoid signaling regulates TCF-1 expression, IL23R signaling, and Th17 pathogenicity; and 3) Determine the role of cell-intrinsic steroidogenesis in opposing Th17 pathogenicity. Our proposed investigation is highly clinically relevant given the association of genetic variants of TCF7 with susceptibility to MS and the use of GCs to treat relapses in patients with relapsing-remitting MS (RR-MS).