Nod2 is a negative regulator of arthritogenic T cell responses in SKG mice

Abstract Nod2 is a pattern recognition receptor known for its role in antimicrobial immunity. Intriguingly, NOD2 appears to have a role outside of infection, as a single point mutation in this molecule leads to 100% incidence of an inflammatory arthritis called Blau Syndrome. Here we investigate the role of Nod2 in regulation of arthritogenic CD4+ T cells in SKG mice. SKG mice have a mutation in ZAP-70 that results in altered thymic selection and spontaneous production of arthritogenic T cells. Nod2−/− SKG mice have exacerbated arthritis and increased numbers of CD4+IL-17+ (Th17) cells that co-produce TNF and GM-CSF compared to SKG mice. Additionally, Nod2−/− SKG mice have augmented levels of IL-17A in their joint synovial fluid. Exacerbated disease in Nod2−/− SKG mice is independent of sex or SKG-mediated dysbiosis as shown by co-housing studies, but dependent on the skg-mutation. Naïve (non-arthritic) Nod2−/− SKG mice have similar numbers of conventional CD4+ T cells with unaltered Treg frequency or function compared to SKG mice. However, CD4+ T cells isolated from naïve Nod2−/− SKG mice produce increased levels of pro-inflammatory cytokines (IL-17, IFNγ) in response to TCR-dependent or -independent stimulus. Furthermore, transfer of CD4+ T cells isolated from naïve Nod2−/−SKG mice into lymphopenic (Nude) recipients results in worsened arthritis compared to an analogous transfer of SKG-CD4+ T cells. These data suggest a previously unappreciated function of Nod2 as a negative regulator of the proinflammatory capacity and pathogenesis of autoreactive CD4+ T cells in SKG mice. Understanding how Nod2 participates in immune tolerance mechanisms will contribute to our knowledge of the pathophysiology of autoimmunity and arthritis.