Dissecting functions of IL-23-dependent inflammatory Th17 cells

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Project Summary Although IL-17-producing T helper (Th17) cells are a major pathogenic contributor to autoimmune diseases, functional diversity undermines their potential as a prospective target for treating autoimmunity. Th17 cells are currently classified into homeostatic and inflammatory subpopulations. It was noted that inflammatory Th17 cells can be beneficial (anti-infection) and pathogenic (pro-autoimmunity). The distinction between homeostatic and inflammatory Th17 cells has been extensively studied. However, how to dissect the anti-infection and pro- autoimmunity functions of inflammatory Th17 cells is largely unknown. There is a critical need for this knowledge given serious infections and fatal outcomes observed in patients receiving general inhibitors of inflammatory Th17 cells (e.g. antibodies against IL-23). Herein, autoimmune and anti-infection subsets of inflammatory Th17 cells are for the first time distinguished experimentally. The objective of this grant is to elucidate the metabolic regulation discriminating autoimmune and anti-infection Th17 cells derived from murine models and human patients. The central hypothesis is that autoimmune and anti-infection Th17 subsets adopt distinct serine metabolic programming. The rationale is that determining the differences between autoimmune and anti-infection Th17 subsets will offer opportunities for novel therapeutics with substantially improved selectivity than the current regimens. The central hypothesis will be tested by pursuing three specific aims: 1) to determine the mechanism for regulating serine metabolism in the autoimmune Th17 subset; 2) to determine the mechanism by which serine regulates pathogenicity of the autoimmune Th17 subset; and 3) to determine the transcriptional and metabolic programming of Th17 cells from patients with inflammatory bowel disease (IBD). Under the first aim, autoimmune Th17 cells recovered from murine models will be used to measure intracellular serine and indicators of autoimmune pathogenicity with modulation of serine metabolic enzymes. For the second aim, biochemical approaches and murine models will be employed to evaluate the relationship between serine-induced intracellular methylation and pathogenic potential of Th17 cells. In the third aim, RNA-seq analysis will be performed to evaluate transcription profiles of Th17 cells from IBD patients. The research proposed in this application is innovative, because it focuses on the immunometabolic regulation discriminating anti-infection and autoimmune Th17 subsets, a heretofore-unexamined mechanism. The proposed research is significant because it is expected to provide novel opportunities to develop autoimmune Th17-selective therapeutics for autoimmune diseases. This would be extraordinarily important for patients that have been infected or exposed to certain pathogens, such as tuberculosis, since existing Th17 inhibitors cannot be used due to the risks of decreasing the patients’ control of the infection.