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Ellen J Lee, Ruth Napier, Emily Vance, Kimberly Samson, Sydney Lashley, Mary J Mattapallil, Justine R Smith, Rachel R Caspi, Holly Lallman Rosenzweig; Nod2 limits autoimmunity to the neuroretina through a T cell-intrinsic mechanism. Invest. Ophthalmol. Vis. Sci. 2019;60(9):767. doi: https://doi.org/.
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NOD2 is an innate immune receptor whose antimicrobial functions in antigen-presenting cells (APCs) are well-described. Importantly NOD2 is also linked to ocular immune homeostasis, as mutations in NOD2 cause non-infectious uveitis. We previously reported a protective role for Nod2 expressed in hematopoietic cells in mitigation of Th17 responses in experimental autoimmune uveitis (EAU). Here, we sought to delineate the cell-specific role for Nod2 (i.e. T cell-intrinsic vs -independent) in suppression of Th17 responses and uveitis.
To assess the role of Nod2 in APCs vs. T cells, in vitro APC/T cell criss-cross experiments were performed using APCs sufficient or deficient for Nod2. The IL-17 response to IRBP stimulation was measured (ELISA). The T cell-intrinsic function of Nod2 in vivo was assessed in Rag1-/- mice reconstituted with CD4+ T cells of naïve wild-type (WT, C57BL/6) or Nod2-/- mice, immunized for EAU, and evaluated by fundus imaging and histology (n=24-28 total/group, 6 repeats). At 28d post-immunization, activation state of T cells (i.e. CD62L, CD69, CD44 expression) and IRBP-specific IL-17 production were also evaluated (flow cytometry, ELISA). To assess a T cell-independent role for Nod2, the converse study was performed with CD4+ T cells of naïve WT mice transferred into Rag1-/- vs. Rag1-/-Nod2-/- recipients who were then immunized for EAU. Data were analyzed by Mann-Whitney or Student’s t-tests, and p<0.05 were considered significant.
APC/T cell criss cross experiments showed that IRBP-induced IL-17 production was controlled by Nod2 in T cells, irrespective of APC genotype. Rag1-/- mice reconstituted with Nod2-/- CD4+ T cells developed increased severity (p<0.05, d14-28) and earlier onset of uveitis compared to those with WT CD4+ T cells; whereas WT CD4+ T cell-recipients (i.e. Rag1-/- or Rag1-/-Nod2-/- mice) developed comparable uveitis. Importantly, T cells isolated from Nod2-/- CD4+ T cell recipients expressed lower levels of CD62L and higher levels of CD69, consistent with a more activated state, and produced increased levels of IL-17 in response to IRBP.
In autoimmune uveitis, Nod2 acts as an intrinsic regulator of T cells by inhibiting antigen-specific IL-17 production, activation, and pathogenicity. These functions for Nod2 are unique from its conventional roles described in APCs and could suggest novel strategies for uveitis treatment.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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