ACR Meeting Abstracts

ACR Meeting Abstracts

  • Home
  • Meetings Archive
    • ACR Convergence 2022
    • ACR Convergence 2021
    • ACR Convergence 2020
    • 2020 ACR/ARP PRSYM
    • 2019 ACR/ARP Annual Meeting
    • 2018 ACR/ARHP Annual Meeting
    • 2017-2009 Meetings
    • Download Abstracts
  • Keyword Index
  • Advanced Search
  • Your Favorites
    • Favorites
    • Login
    • View and print all favorites
    • Clear all your favorites
  • Meeting Resource Center

Abstract Number: 2700

Fra-2 Overexpression Leads to Systemic Autoimmunity By Affecting IL2 Dependent Treg Homeostasis

Florian Renoux1, Mara Stellato1, Daniela Impellizzieri2, Alexander Vogetseder3, Przemyslaw Blyszczuk1, Riyun Huang4, Arun Subramaniam5, Clara Dees6, Jörg Distler7, Gabriela Kania1, Onur Boyman2 and Oliver Distler8, 1Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland, 2Division of Clinical Immunology, University Hospital Zurich, Zurich, Switzerland, 3Department of Pathology, Cantonal Hospital Lucerne, Lucerne, Switzerland, 4Immune Mediated Diseases, Sanofi-Genzyme, Framingham, MA, 5Sanofi-Genzyme, Framingham, MA, 6Department of Internal Medicine 3 and Institute for Clinical Immunology,, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Germany, 7Department of Internal Medicine 3 – Rheumatology and Immunology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Germany, 8Department of Rheumatology, Center of Experimental Rheumatology, University Hospital Zurich, Zurich, Switzerland

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: immunity, inflammation and mouse model, T cells, T-Regulatory Cells

  • Tweet
  • Email
  • Print
Session Information

Date: Tuesday, November 7, 2017

Session Title: T Cell Biology and Targets in Autoimmune Disease Poster II

Session Type: ACR Poster Session C

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

Background/Purpose: Fos-related antigen 2 (Fra-2) is a transcription factor belonging to the Fos family proteins which is part of the AP-1 transcription factor complex. We recently described a fra-2 transgenic (tg) mouse model which develops a multi-organ inflammatory phenotype. We have observed abnormalities in the T cell compartment, which led us to hypothesize that fra-2tg mice develop a T cell-driven autoimmune phenotype.

Here we aimed to assess the autoimmune nature of the phenotype in fra-2tg mice and to characterize the potential role of Treg cells.

Methods: We used previously generated fra-2tg overexpressing mice. T lymphocyte populations were analyzed by flow cytometry for expression of activation markers (CD62L, CD44 and CD25) and secretion of cytokines. We transferred purified CD4+ T cells into Rag2-/- mice lacking T and B cells, and we generated Rag2-/-fra-2tg mice. We used IL-2-IL-2 antibody complexes (JES6.1A12 clone) to induce the proliferation of CD25+ cells in vivo.

Results: Rag2-/-fra-2tg  did not develop inflammatory manifestations (n=10), demonstrating that the phenotype in fra-2tg mice is autoimmune and requires the presence of T and/or B cells to develop. Accordingly, we tested the ability of CD4+ T cells to induce the phenotype. We found that the transfer of 1*106 purified CD4+ cells from 16 week-old fra-2tg mice into Rag2-/- recipients was sufficient to induce the phenotype (n=3).

Analysis of T cell populations from fra-2tg mice confirmed the presence of activated CD4+ and CD8+ cells in spleen and lung (n=6). After in vitro stimulation, CD4+ T cells from fra-2tg mice had increased Th2 cytokines production (IL-4, IL-5 and IL-13) and we observed an increase in IgE levels in the serum of fra-2tg mice. Thus, these data strongly suggest a Th2 T cell-driven autoimmune disease in these mice.

            We also observed a striking decrease of Treg cells in fra-2tg mice, which might explain the observed autoimmune phenotype. Supporting this hypothesis, we found that 3 week-old mice, which were devoid of organ manifestations and of T cell activation, showed already the same defect in the Treg cell population as older mice (n=6, p<0.001).

Interestingly, we also found that in vivo stimulation with IL-2-IL-2 antibody complexes failed to induce the proliferation of Treg cells in fra-2tg mice compared to WT mice, suggesting that fra-2 overexpression affects IL-2 dependent proliferation of fra-2tg Tregs. These data indicate that Fra-2 affects Treg homeostasis by modulating IL-2 responsiveness, resulting in the development of an autoimmune phenotype.

 

Conclusion: Our data suggest that Fra-2 controls Treg cell development or homeostasis, possibly by modulating IL-2 signaling in T cells, which leads to autoimmunity in this mouse model. This new pathway could be targeted in a translational approach to modulate the capacity of T cells to differentiate in Tregs during autoimmune disease.  

 

 


Disclosure: F. Renoux, None; M. Stellato, None; D. Impellizzieri, None; A. Vogetseder, None; P. Blyszczuk, None; R. Huang, Sanofi-genzyme, 3; A. Subramaniam, Sanofi-genzyme, 3; C. Dees, None; J. Distler, 4D Science, 1,Anamar Medical, Active Biotech, Array Biopma, BMS, Bayer Pharma, Boehringer Ingelheim, Celgene, GSK, Novartis, Sanofi-Aventis, UCB, 2,Actelion Pharmaceuticals US, Active Biotech, Anamar, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, JB Therapeutics, Medac, Pfizer, RuiYi, UCB, 5; G. Kania, Bayer, 2; O. Boyman, None; O. Distler, Actelion, Bayer, BiogenIdec, Boehringer Ingelheim, ChemomAb, espeRare foundation, Genentech/Roche, GSK, Inventiva, Lilly, medac, MedImmune, Mitsubishi Tanabe Pharma, Pharmacyclics, Novartis, Pfizer, Sanofi, Sinoxa and UCB, 2,Actelion, Bayer, BiogenIdec, Boehringer Ingelheim, ChemomAb, espeRare foundation, Genentech/Roche, GSK, Inventiva, Lilly, medac, MedImmune, Mitsubishi Tanabe Pharma, Pharmacyclics, Novartis, Pfizer, Sanofi, Sinoxa and UCB, 5,mir-29 for the treatment of systemic sclerosis, 9.

To cite this abstract in AMA style:

Renoux F, Stellato M, Impellizzieri D, Vogetseder A, Blyszczuk P, Huang R, Subramaniam A, Dees C, Distler J, Kania G, Boyman O, Distler O. Fra-2 Overexpression Leads to Systemic Autoimmunity By Affecting IL2 Dependent Treg Homeostasis [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/fra-2-overexpression-leads-to-systemic-autoimmunity-by-affecting-il2-dependent-treg-homeostasis/. Accessed February 6, 2023.
  • Tweet
  • Email
  • Print

« Back to 2017 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/fra-2-overexpression-leads-to-systemic-autoimmunity-by-affecting-il2-dependent-treg-homeostasis/

Advanced Search

Your Favorites

You can save and print a list of your favorite abstracts during your browser session by clicking the “Favorite” button at the bottom of any abstract. View your favorites »

ACR Pediatric Rheumatology Symposium 2020

© COPYRIGHT 2023 AMERICAN COLLEGE OF RHEUMATOLOGY

Wiley

  • Home
  • Meetings Archive
  • Advanced Search
  • Meeting Resource Center
  • Online Journal
  • Privacy Policy
  • Permissions Policies
  • Cookie Preferences