Nod2 deficiency augments Th17 responses and exacerbates autoimmune arthritis

Ruth J. Napier, Ellen J. Lee, Emily E. Vance, Paige E. Snow, Kimberly A. Samson, Clare E. Dawson, Amy E. Moran, Peter Stenzel, Michael P. Davey, Shimon Sakaguchi, Holly L. Rosenzweig

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


Arthritis in a genetically susceptible SKG strain of mice models a theoretical paradigm wherein autoimmune arthritis arises because of interplay between preexisting autoreactive T cells and environmental stimuli. SKG mice have a point mutation in ZAP-70 that results in attenuated TCR signaling, altered thymic selection, and spontaneous production of autoreactive T cells that cause arthritis following exposure to microbial b-glucans. In this study, we identify Nod2, an innate immune receptor, as a critical suppressor of arthritis in SKG mice. SKG mice deficient in Nod2 (Nod22/2SKG) developed a dramatically exacerbated form of arthritis, which was independent of sex and microbiota, but required the skg mutation in T cells. Worsened arthritis in Nod22/2 SKG mice was accompanied by expansion of Th17 cells, which to some measure coproduced TNF, GM-CSF, and IL-22, along with elevated IL-17A levels within joint synovial fluid. Importantly, neutralization of IL-17A mitigated arthritis in Nod22/2SKG mice, indicating that Nod2-mediated protection occurs through suppression of the Th17 response. Nod2 deficiency did not alter regulatory T cell development or function. Instead, Nod2 deficiency resulted in an enhanced fundamental ability of SKG CD4+ T cells (from naive mice) to produce increased levels of IL-17 and to passively transfer arthritis to lymphopenic recipients on a single-cell level. These data reveal a previously unconsidered role for T cell-intrinsic Nod2 as an endogenous negative regulator of Th17 responses and arthritogenic T cells. Based on our findings, future studies aimed at understanding a negative regulatory function of Nod2 within autoreactive T cells could provide novel therapeutic strategies for treatment of patients with arthritis.

Original languageEnglish (US)
Pages (from-to)1889-1898
Number of pages10
JournalJournal of Immunology
Issue number7
StatePublished - Oct 1 2018

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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