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 and Holly L. Rosenzweig ()
Additional contact information
Ruth J. Napier: VA Portland Health Care System
Ellen J. Lee: VA Portland Health Care System
Michael P. Davey: VA Portland Health Care System
Emily E. Vance: VA Portland Health Care System
João M. Furtado: University of São Paulo
Paige E. Snow: Oregon Health and Science University
Kimberly A. Samson: Providence Cancer Institute
Sydney J. Lashley: VA Portland Health Care System
Brieanna R. Brown: Providence Medical Group
Reiko Horai: Laboratory of Immunology, NEI, NIH
Mary J. Mattapallil: Laboratory of Immunology, NEI, NIH
Biying Xu: Laboratory of Immunology, NEI, NIH
Michelle C. Callegan: University of Oklahoma Health Sciences Center
Luke S. Uebelhoer: Oregon Health and Science University
Christina L. Lancioni: Oregon Health and Science University
Richard K. Vehe: University of Minnesota and the University of Minnesota Masonic Children’s Hospital
Bryce A. Binstadt: University of Minnesota and the University of Minnesota Masonic Children’s Hospital
Justine R. Smith: Flinders University
Rachel R. Caspi: Laboratory of Immunology, NEI, NIH
Holly L. Rosenzweig: VA Portland Health Care System

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-18961-0

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