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.
Bibliographical noteFunding Information:
This work was supported by the following funding sources: National Institutes of Health (EY025250, EY025039 to H.L.R.), Department of Veterans Affairs, Biomedical Laboratory Research and Development Service (Merit award I01 BX002180 to H.L.R. and Career Development Award 1 IK2 BX004523 to R.J.N.), Medical Research Foundation of Oregon (R.J.N.), the Gerlinger Foundation (H.L.R.), Portland VA Research Foundation (PVARF), National Eye Institute intramural support (EY00184), and Australian Research Council (FT130101648). The authors thank those at the VA Portland Health Care System for their technical support: Dr. Jae W. Dugan, Dr. David J. Hinrichs, Beatitude Steffen, Samantha Ward. The authors thank Dr. Michael Elliott, Dr. Phillip S. Coburn, and Craig Land (Live Animal Imaging and Analysis Core, P30EY021725, Dean A. McGee Institute, University of Oklahoma Health Sciences Center) for their input, protocols, and technical contributions, as well as Sara Kramer (University of Minnesota) for her help in acquiring samples from Blau syndrome patients. The contents of this manuscript do not represent the views of the U.S. Department of Veterans Affairs or the United States Government.