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Abstract Number: 1412

A T Cell Intrinsic Role for Nod2 in Suppression of Th17-Mediated Experimental Arthritis and Uveitis: Implications for Blau Syndrome

Ruth Napier1, Ellen Lee1, Emily Vance1, Sydney Lashley2, Luke Uebelhoer3, Christina Lancioni3, Richard Vehe4, Bryce Binstadt4, Rachel Caspi5 and Holly Rosenzweig1, 1Oregon Health & Science University and VA Portland Health Care System, Portland, OR, 2VA Portland Health Care System, Portland, OR, 3Oregon Health & Science University, Portland, 4University of Minnesota, Minneapolis, MN, 5NIH, Bethesda, MD

Meeting: ACR Convergence 2020

Keywords: autoimmune diseases, Autoinflammatory diseases, rheumatoid arthritis, T Cell, TH17 Cells

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Session Information

Date: Sunday, November 8, 2020

Session Title: T Cell Biology & Targets in Autoimmune & Inflammatory Disease Poster

Session Type: Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose: Mutations in nucleotide-binding oligomerization domain-containing protein 2 (NOD2) cause Blau syndrome, an inflammatory disorder characterized by uveitis, dermatitis, and polyarthritis. The antimicrobial functions of NOD2 are well established; yet the mechanism by which dysregulated NOD2 causes sterile inflammation remain unknown. Here we utilized experimental models of autoimmune arthritis and uveitis, and PBMCs from Blau syndrome patients to dissect a T cell-specific role for NOD2 in uveitis.

Methods: Arthritis was induced in SKG and NOD2-/-SKG mice with a single intraperitoneal 1.5mg injection of zymosan and assessed by clinical scoring, near infrared imaging and histology. Uveitis was induced in NOD2+/+ and NOD2-/- C57BL/6 mice by immunization with the retinal antigen interphotoreceptor retinoid-binding protein (IRBP) and assessed by clinical scoring and histology. Mice were treated with IL-17A/F mAb (R&D systems) beginning 24h prior to disease induction. Lymphopenic Rag1-/- mice were reconstituted with NOD2-/- or NOD2+/+ (WT) CD4+ T cells and arthritis or uveitis was induced. IL-17 production by T cells was evaluated by flow cytometry and ELISA. For T cell homeostasis studies, purified naive (CD62LhiCD44–) CD4+ T cells were differentiated under Th17 polarizing conditions (CellXVivo) or purified memory (CD62L–CD44hi) CD4+ T cells from naive mice were stimulated with anti-CD3 and anti-CD28, and activation state (CD69) and pro-inflammatory cytokine production was determined by flow cytometry (n≥6 mice/group and repeated 3X). Peripheral blood mononuclear cells from Blau Syndrome patients or healthy controls were cultured for 5 d, stimulated with PMA/ionomycin, and IL-17 was measured. Data were analyzed by Mann-Whitney, and p< 0.05 were considered significant.

Results: Lymphopenic recipients of NOD2-deficient T cells developed significantly worse arthritis and uveitis, implicating T cell-intrinsic NOD2 in suppression of disease. CD4+ T cells purified from arthritic and uveitic mice produced significantly more IL-17, and blockade of IL-17 mitigated the enhanced disease caused by NOD2-deficiency, indicating a direct role for T cell-intrinsic NOD2 in suppressing autoreactive Th17 responses. NOD2 was dispensable for Th17 differentiation of naïve CD4+ T cells. However, NOD2-/- memory (antigen-experienced) CD4+ T cells isolated from naïve mice when stimulated with anti-CD3 and anti-CD28 had enhanced expression of IL-17, the IL-17-associated transcription factor (RORγt) and the activation marker CD69. Importantly, stimulation of CD4+ T cells from Blau syndrome patients resulted in significantly more IL-17 production than those from healthy control T cells, suggesting a similar function for NOD2 in human disease.

Conclusion: We have uncovered a novel, T cell-intrinsic function for NOD2 as a negative regulator of T cell homeostasis and autoimmunity. Our work suggests that a “loss-of-function” in NOD2 (i.e. NOD2-/- mice) results in a “gain-of-function” in the ability of T cells to produce IL-17 and cause arthritis and uveitis. These findings could potentially change the way we view the immunopathology of Blau syndrome and open up new therapeutic options for patients.


Disclosure: R. Napier, None; E. Lee, None; E. Vance, None; S. Lashley, None; L. Uebelhoer, None; C. Lancioni, None; R. Vehe, None; B. Binstadt, None; R. Caspi, None; H. Rosenzweig, None.

To cite this abstract in AMA style:

Napier R, Lee E, Vance E, Lashley S, Uebelhoer L, Lancioni C, Vehe R, Binstadt B, Caspi R, Rosenzweig H. A T Cell Intrinsic Role for Nod2 in Suppression of Th17-Mediated Experimental Arthritis and Uveitis: Implications for Blau Syndrome [abstract]. Arthritis Rheumatol. 2020; 72 (suppl 10). https://acrabstracts.org/abstract/a-t-cell-intrinsic-role-for-nod2-in-suppression-of-th17-mediated-experimental-arthritis-and-uveitis-implications-for-blau-syndrome/. Accessed January 22, 2021.
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