Th17 tissue metab · Metabolic imprinting of Th17 cells in disease pathogenesis

Metabolic imprinting of Th17 cells in disease pathogenesis

Autoimmune diseases are estimated to affect 3-9% of the population1 and cause major personal and socio-economic consequences. Aberrant activation of the immune system occurs and results in immune cell recruitment and inflammation in tissues2. One cell type that is involved in pathogenesis of multiple autoimmune diseases are IL-17-producing CD4+ T cells (Th17), which also produce additional pathogenic cytokines3. The overall aim of this project is to gain insight into Th17 cell functions, their involvement in autoimmune disease pathogenesis and identification of novel targets for drug development. Targets will be validated in the context of multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system (CNS) and leading cause of non-traumatic disability in young adults. Currently, no cure exists but a variety of treatments are available that improve life quality and reduce relapse rates4. Multiple therapies were based on findings from the mouse model for MS, experimental autoimmune encephalomyelitis (EAE)5. Th17 cells accumulate in CNS lesions of MS patients6 and drive disease pathogenesis in mice with EAE7,8. In general, Th17 cells are found in lymphoid tissues and inflamed tissue sites (e.g. CNS). However, Th17 cells were more recently also described in non-lymphoid tissues (termed “tissue Th17 cells”), where they exert homeostatic functions in the healthy state9-12. Thus, Th17 cells might be distinct in different tissues. How tissue Th17 cells acquire their specialized characteristics in diverse tissues remains elusive. We hypothesize that Th17 cells require metabolic cues from their tissue environment that instruct their tissue-specific phenotype. Thus, metabolic manipulation would be a promising approach to turn pathogenic tissue Th17 cells into homeostatic ones, reducing their pathogenicity. Several studies suggest that Th17 cells reside in or are primed at different tissue locations from where they can be recruited to sites of autoimmune inflammation, such as the CNS13-16. Thus, the metabolic environment in the tissue of origin might imprint pathogenic Th17 potential. Th17 cells are indeed implicated in disease pathogenesis in a variety of tissues, including skin, lung and gut17-19. Identifying tissue-specific metabolic switches for Th17 pathogenicity might thus pave the way for the development of novel treatment options for MS and other autoimmune diseases. Metabolism was recently shown to play a role in Th17 cell function20-24, among others by the Kuchroo lab25,26. However, only isolated metabolic pathways have been examined, often restricted to single tissues or in vitro studies. Thus, a comprehensive, unbiased study on Th17 cells across all tissues is required, which provides a systematic understanding of tissue specific Th17 metabolism during homeostasis and an autoimmune reaction. Building on sound preliminary data from the gut, I will expand to a cross-tissue explorative single cell RNA-seq (scRNAseq) study with metabolic flux analysis and will validate targets in mouse models, as defined in the following objectives: O1) What defines Th17 cells in different tissues and what are their metabolic requirements in health and disease? O2) Which metabolic pathways are regulators of tissue specific Th17 cell function? O3) Can specific metabolic regulators prevent Th17 mediated diseases and if so how?

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