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).