T cell intrinsic role for NOD2 in Blau Syndrome

Abstract

Abstract Children with mutations in the nucleotide binding domain of NOD2 cause the monogenetic inflammatory disease Blau Syndrome, which is characterized by dermatitis, arthritis and uveitis. NOD2 is a well-known microbial sensor important in anti-bacterial immunity. However, the mechanism by which mutated NOD2 causes non-infectious inflammation in Blau is unknown. We recently reported a novel function of Nod2 as a central regulator of T cell homeostasis and as a negative regulator of autoreactive Th17 responses in experimental autoimmune uveitis (EAU) and arthritis. Here, we examined the effect of Blau mutations on T cell function and EAU using Blau knock-in mice carrying the most common Blau-mutation R314Q (corresponding to R334Q in humans) and Blau patient cells. We found that CD4+ T cells from Blau patients and Blau mice, produced increased IL-17 but decreased IFNγ following in vitro TCR-activation compared to control patients and WT mice, respectively. Blau mice developed worsened EAU compared to WT controls, which was accompanied by increased autoreactive (retina-specific) Th17 cells within the eye. Lymphocyte-deplete Rag1−/− mice reconstituted with Blau CD4+ T cells developed worse EAU than WT T cell recipients, indicating that CD4+ T cells expressing Blau-specific Nod2 mutations are sufficient to cause exacerbated EAU. Cumulatively, these data reveal a previously unconsidered role for Th17 cells in Blau Syndrome, and provide new T cell-targeted therapeutic avenues to treat this disease. Supported by grants from VA (CDA-2 IK2BX004523 and Merit I01BX002180) and NIH (R01 EY025250).