T-cell intrinsic RIP2 regulates pathogenic Th17 differentiation in chronic lung and vascular inflammation

Abstract

Abstract RIP2 plays a role in sensing intracellular pathogens as an adaptor molecule for NOD1 and NOD2 intracellular receptors. While these pathways are present in many cells types, the role of RIP2 in T-cells has been much less studied. Th17 cells are a subset of CD4+ T-helper cells that produce IL17A. While Th17 cells and IL17A play an important protective role at mucosal surfaces under homeostatic conditions, and are important for immunity against certain pathogens, aberrant Th17 responses can lead to severe and chronic inflammatory diseases. Using a Chlamydia pneumoniae lung infection model, we found that Rip2 deficiency led to chronic and severe IL17A mediated inflammation. This was a T-cell intrinsic effect as naive Rip2−/− CD4+ T-cells transferred into Rag1− /− mice resulted in increased Th17 cell formation in the lungs of C. pneumoniae infected mice. This was further confirmed in an atherosclerosis model, in which naive Rip2−/− CD4+ T-cells transferred into Rag1−/− mice caused exacerbated disease, which was IL17A dependent. Intriguingly, our in vitro studies found that while RIP2 deficiency resulted in reduced Rorc expression and reduced homeostatic Th17 differentiation, loss of RIP2 also led to significantly enhanced differentiation of pathogenic Th17 cells, which was RORa dependent, but NOD1 and NOD2 independent. Conversely, overexpression of Rip2 resulted in suppression of pathogenic Th17 differentiation, which was independent of RIP2 kinase activity. Taken together, we have discovered a novel T-cell intrinsic mechanism for RIP2 in regulating the balance between pathogenic and homeostatic Th17 cells. This has broad-reaching implications for many chronic inflammatory diseases where IL17A plays a major role.