Impact of co-inhibitory receptors on Th17 differentiation and pathogenicity

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Interleukin-17 producing T helper cells (Th17) cells are linked to the pathogenesis of highly prevalent inflammatory diseases like multiple sclerosis (MS) and rheumatoid arthritis (RA). Anti-IL-17 antibody therapy has shown promising results in the treatment of several autoimmune diseases, but it also worsened disease outcome e.g. in intestinal bowel diseases. Recent discoveries imply that this observed dichotomy is caused due to two different subtypes of Th17 cells, one that induces autoimmunity (pathogenic) and one that does not (non-pathogenic). How these two Th17 phenotypes are regulated in detail is not known, neither is the role of inhibitory molecules in Th17 cell pathogenicity. Previous work suggests that Protein C Receptor (PROCR), which is selectively enriched on non-pathogenic Th17 cells, and programmed cell death protein 1 (PD-1) promote Th17 cell differentiation, but once expressed inhibit effector functions of Th17 cells. This research project addresses the question how these inhibitory molecules regulate Th17 induction and functions. It will be analyzed whether they do not only inhibit pathogenic Th17 cells but also promote differentiation of non-pathogenic Th17 cells. Using PROCR hypomorphic mutant mice and PD-1 knockout mice it will be studied whether PROCR and PD-1 do synergize when controlling effector functions of Th17 cells. Whether changes to the pathogenic signature of Th17 cells induced by PROCR or PD-1 also translate into altered pathogenicity in vivo will be tested using experimental autoimmune encephalomyelitis (EAE), the most common animal model of MS. Several mutants of the PROCR ligand, activated protein C (aPC), which have selective anti-coagulant and/or anti-inflammatory effects, will be tested regarding their effect on Th17 differentiation and their ability to convert pathogenic Th17 cells into non-pathogenic Th17 cells. It will be examined whether aPC can thereby alter the clinical course of EAE. This project will therefore give crucial insights on differentiation and regulation of pathogenic and non-pathogenic Th17 phenotypes and will help to identify specific targets to selectively inhibit pathogenic but spare protective Th17 cells.