July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
Nod2 is a T cell-intrinsic suppressor of Th17 cell-mediated uveitis
Author Affiliations & Notes
  • Ellen J Lee
    Portland VAMC, Mail code: R&D 14, Oregon Health & Science University, Portland, Oregon, United States
    Molecular Microbiology & Immunology, Oregon Health & Science University, Portland, Oregon, United States
  • Ruth Napier
    Portland VAMC, Mail code: R&D 14, Oregon Health & Science University, Portland, Oregon, United States
    Molecular Microbiology & Immunology, Oregon Health & Science University, Portland, Oregon, United States
  • Paige Snow
    Portland VAMC, Mail code: R&D 14, Oregon Health & Science University, Portland, Oregon, United States
  • Emily Vance
    Portland VAMC, Mail code: R&D 14, Oregon Health & Science University, Portland, Oregon, United States
    Molecular Microbiology & Immunology, Oregon Health & Science University, Portland, Oregon, United States
  • Kimberly Samson
    Portland VAMC, Mail code: R&D 14, Oregon Health & Science University, Portland, Oregon, United States
    Molecular Microbiology & Immunology, Oregon Health & Science University, Portland, Oregon, United States
  • Mary Mattapallil
    National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States
  • Joao Furtado
    Department of Ophthalmology, University of São Paulo, Sao Paulo, Brazil
  • Justine R. Smith
    School of Medicine, Flinders University, Adelaide, South Australia, Australia
  • Rachel R Caspi
    National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States
  • Holly Rosenzweig
    Portland VAMC, Mail code: R&D 14, Oregon Health & Science University, Portland, Oregon, United States
    Molecular Microbiology & Immunology, Oregon Health & Science University, Portland, Oregon, United States
  • Footnotes
    Commercial Relationships   Ellen Lee, None; Ruth Napier, None; Paige Snow, None; Emily Vance, None; Kimberly Samson, None; Mary Mattapallil, None; Joao Furtado, None; Justine Smith, None; Rachel Caspi, None; Holly Rosenzweig, None
  • Footnotes
    Support  National Institutes of Health (RO1 EY025250, EY025039); Intramural funding from National Eye Institute (Project# EY00184); Merit Review Award (I01 BX002180) from the Department of Veterans Affairs Biomedical Laboratory Research & Development Service; Australian Research Council (FT130101648)
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 2551. doi:
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    • Get Citation

      Ellen J Lee, Ruth Napier, Paige Snow, Emily Vance, Kimberly Samson, Mary Mattapallil, Joao Furtado, Justine R. Smith, Rachel R Caspi, Holly Rosenzweig; Nod2 is a T cell-intrinsic suppressor of Th17 cell-mediated uveitis. Invest. Ophthalmol. Vis. Sci. 2018;59(9):2551.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : The innate immune receptor nucleotide-binding oligomerization domain (NOD)-like receptor 2 (NOD2) is important in host defense, but is also the genetic cause of uveitis called Blau syndrome. Prior studies revealed a protective role for Nod2 in experimental autoimmune uveitis (EAU) via mitigation of the Th17 response. Here, we probed the effect of Nod2 on T cell responses in experimental uveitis and the cell population from which it operates.

Methods : Wild-type C57BL/6J or Nod2 KO mice were immunized for EAU with interphotoreceptor retinoid-binding protein (IRBP) and IRBP1-20 peptide. Purified CD4+ T cells were evaluated for Nod2 expression (RT-PCR) and Th17-associated transcripts (RT2Profiler). Pathogenicity of CD4+ T cells from immunized WT or Nod2 KO mice was evaluated by adoptive transfer into naive WT recipients. The cell lineage with the essential Nod2 function was evaluated in bone marrow (BM) chimeric mice immunized for EAU. IRBP-induced IL-17 production from in vitro APC/T cell criss-cross experiments was measured by ELISA. To evaluate a T cell-intrinsic function of Nod2, Rag1 KO mice were reconstituted with CD4+ T cells from naïve WT or Nod2KO mice, immunized for EAU, and monitored for uveitis. After 4 wks, CD4+ T cells were evaluated for activation markers (flow cytometry) and IL-17 production (ELISA). Data were analyzed by Mann-Whitney or Student’s t test (n≥6 mice/group, repeated once), and p<0.05 were considered significant.

Results : Naïve T cells express Nod2. IRBP-stimulated Nod2 KO CD4+ T cells exhibited enhanced expression of Th17-associated genes and a distinct transcriptional profile. Adoptive transfer studies demonstrated enhanced capacity of Nod2 KO CD4+ T cells to initiate disease. BM chimera and criss-cross studies suggested a T cell, rather than APC, function for Nod2 in controlling uveitis development and Th17 responses. Studies with Rag1 KO mice further supported a T cell-intrinsic role in that mice with Nod2 KO CD4+ T cells developed more severe uveitis (p<0.001) and had greater numbers of activated CD4+ T cells, which produced higher amounts of IRBP-induced IL-17.

Conclusions : Nod2-controlled suppression of T cell-mediated IL-17 production occurred predominantly within hematopoietic cells, but not via conventional APC activation. Rather, Nod2 operated intrinsically within CD4+ T cells to suppress their pathogenic potential, suggesting that Nod2 is a genetic modifier of T cells in uveitis.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.

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