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T cell-intrinsic role for Nod2 in protection against Th17-mediated uveitis

Napier, RJ;Lee, EJ;Davey, MP;Vance, EE;Furtado, JM;Snow, PE;Samson, KA;Lashley, SJ;Brown, BR;Horai, R;Mattapallil, MJ;Xu, B;Callegan, MC;Uebelhoer, LS;Lancioni, CL;Vehe, RK;Binstadt, BA;Smith, JR;Caspi, RR;Rosenzweig, HL;

Mutations in nucleotide-binding oligomerization domain-containing protein 2 (NOD2) cause Blau syndrome, an inflammatory disorder characterized by uveitis. The antimicrobial functions of Nod2 are well-established, yet the cellular mechanisms by which dysregulated Nod2 causes uveitis remain unknown. Here, we report a non-conventional, T cell-intrinsic function for Nod2 in suppression of Th17 immunity and experimental uveitis. Reconstitution of lymphopenic hosts with Nod2-/- CD4+ T cells or retina-specific autoreactive CD4+ T cells lacking Nod2 reveals a T cell-autonomous, Rip2-independent mechanism for Nod2 in uveitis. In naive animals, Nod2 operates downstream of TCR ligation to suppress activation of memory CD4+ T cells that associate with an autoreactive-like profile involving IL-17 and Ccr7. Interestingly, CD4+ T cells from two Blau syndrome patients show elevated IL-17 and increased CCR7. Our data define Nod2 as a T cell-intrinsic rheostat of Th17 immunity, and open new avenues for T cell-based therapies for Nod2-associated disorders such as Blau syndrome.