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Abstract Number: 1741

Mutated Nod2 Controls T Cell Function and Promotes Uveitis in a Blau Syndrome Mouse Model

Leah Huey1, Kylie Koney1, Emily Vance1, Chia-Feng Tsai2, Rosalie K. Chu2, Marina A. Gritsenko2, Ellen Lee1, Holly Rosenzweig1 and Ruth Napier1, 1Oregon Health & Science University and VA Portland Health Care System, Portland, OR, 2Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA

Meeting: ACR Convergence 2022

Keywords: autoantigens, Autoinflammatory diseases, cytokines, Mouse Models, Other, T Cell

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Session Information

Date: Monday, November 14, 2022

Title: T Cell Biology and Targets in Autoimmune and Inflammatory Disease Poster

Session Type: Poster Session D

Session Time: 1:00PM-3:00PM

Background/Purpose: Mutations in the microbial signaling molecule NOD2 cause granulomatous uveitis, arthritis, and dermatitis in Blau Syndrome. We previously showed a novel role for Nod2 within CD4+ T cells in protection against IL-17-mediated experimental autoimmune uveitis (EAU). Here, we wanted to determine if mice expressing the Nod2 mutation in Blau Syndrome (R334Q) have altered T cell function or disease in uveitis.

Methods: Uveitis was induced in wild type (WT), Nod2-/- mice and mice with heterozygous expression of the Nod2 mutation R314Q (corresponding to R334Q in humans) referred to as Blau mice; or in lymphopenic Nod2+/+Rag1-/- mice reconstituted with WT or Blau CD4+ T cells by immunization with the retinal autoantigen interphotoreceptor retinoid-binding protein (IRBP). Uveitis was assessed by clinical scoring and histology. IL-17 production by ocular-infiltrating T cells was assessed by flow cytometry. RT-qPCR was used to determine NOD2 expression in Jurkat T cells after TCR stimulation with monoclonal antibodies to CD3 and CD28. Mass spectrometry-based global phosphoproteomics was performed on purified CD4+ T cells 20 minutes post-TCR-activation treatment. Data were analyzed by Mann-Whitney or ANOVA, and p< 0.05 were considered significant.

Results: Similar to Nod2-deficient mice (Nod2-/-), Blau mice developed exacerbated uveitis with increased IRPB-specific Th17 cells in the eye compared to WT mice. Blau T cells had enhanced pathogenicity as lymphopenic mice reconstituted with Blau CD4+ T cells developed worse uveitis than those reconstituted with WT CD4+ T cells. Nod2 is expressed by T cells upon autoantigen recognition, yet the role of Nod2 in T cell activation is unknown. Following overnight TCR stimulation, Nod2-/- and Blau CD4+ T cells produced less IL-2 compared to WT, indicating Nod2 controls early T cell activation events. In support, NOD2 mRNA expression was increased within 20 minutes of TCR stimulation in Jurkat T cells. Analysis of global protein phosphorylation events at 20 minutes post stimulation of purified Nod2-/- and Blau CD4+ T cells revealed altered phosphorylation kinetics of the T cell-activating transcription factors Nfkb1 and Nfatc compared to activated WT T cells. We also detected enhanced phosphorylation of the Th17 differentiation mediators Runx1 and IL-21r in Nod2-/- and Blau mice compared to WT, supporting a role for Nod2 in controlling IL-17 signaling in response to TCR stimulation.

Conclusion: Our data show that a Blau Syndrome-associated Nod2 mutation (R334Q) results in loss-of-function in Nod2, which similar to Nod2 deficiency (Nod2-/-), leads to exacerbated T cell-mediated uveitis and defective T cell activation and signaling. Together, our work suggests that a T cell-targeted therapy may be an effective treatment for Blau Syndrome.


Disclosures: L. Huey, None; K. Koney, None; E. Vance, None; C. Tsai, None; R. Chu, None; M. Gritsenko, None; E. Lee, None; H. Rosenzweig, None; R. Napier, None.

To cite this abstract in AMA style:

Huey L, Koney K, Vance E, Tsai C, Chu R, Gritsenko M, Lee E, Rosenzweig H, Napier R. Mutated Nod2 Controls T Cell Function and Promotes Uveitis in a Blau Syndrome Mouse Model [abstract]. Arthritis Rheumatol. 2022; 74 (suppl 9). https://acrabstracts.org/abstract/mutated-nod2-controls-t-cell-function-and-promotes-uveitis-in-a-blau-syndrome-mouse-model/. Accessed .
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