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

Ruth J. Napier, Ellen J. Lee, Michael P. Davey, Emily E. Vance, João M. Furtado, Paige E. Snow, Kimberly A. Samson, Sydney J. Lashley, Brieanna R. Brown, Reiko Horai, Mary J. Mattapallil, Biying Xu, Michelle C. Callegan, Luke S. Uebelhoer, Christina L. Lancioni, Richard K. Vehe, Bryce A. Binstadt, Justine R. Smith, Rachel R. Caspi, Holly L. Rosenzweig

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article number5406
JournalNature communications
Volume11
Issue number1
DOIs
StatePublished - Dec 1 2020

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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