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

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

doi:10.1038/s41467-020-18961-0

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.

Highlights

Mutations in nucleotide-binding oligomerization domain-containing protein 2 (NOD2) cause Blau syndrome, an inflammatory disorder characterized by uveitis
WT (C57BL/6J) and Nod2−/− mice were immunized with interphotoreceptor retinoid-binding protein (IRBP) and monitored clinically by fundoscopy for development of uveitis (Fig. 1a, b)
A prevailing theory proposes that uveitis involves innate signals arising from early microbial-genetic interactions that engender a break in T cell tolerance

Summary

Introduction

Mutations in nucleotide-binding oligomerization domain-containing protein 2 (NOD2) cause Blau syndrome, an inflammatory disorder characterized by uveitis. The antimicrobial functions of Nod[2] are well-established, yet the cellular mechanisms by which dysregulated Nod[2] causes uveitis remain unknown. We report a non-conventional, T cell-intrinsic function for Nod[2] in suppression of Th17 immunity and experimental uveitis. Nod[2] operates downstream of TCR ligation to suppress activation of memory CD4+ T cells that associate with an autoreactive-like profile involving IL-17 and Ccr[7]. Our data define Nod[2] 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. Like receptors (NLRs), which are intracellular innate receptors vital to host defense against infection and toxic substances[3]; it is thought that such diseases arise from dysfunction in innate immunity

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Results

Conclusion