Multi-faceted inhibition of dendritic cell function by CD4+Foxp3+ regulatory T cells. (March 2019)

• Record Type: Journal Article
• Authors: Seitz, Christina; Liu, Sang; Klocke, Katrin; Joly, Anne-Laure; Czarnewski, Paulo V.; Tibbitt, Christopher A.; Parigi, Sara M.; Westerberg, Lisa S.; Coquet, Jonathan M.; Villablanca, Eduardo J.; Wing, Kajsa; Andersson, John
• Is Part Of: Journal of autoimmunity. Volume 98(2019)
• Page Start: 86
• Page End: 94
• Publication Date: 2019-03
• Subjects: Regulatory T cells -- Dendritic cells -- Costimulation -- CTLA-4 -- PD-L2; Autoimmunity -- Periodicals; Autoimmune diseases -- Periodicals; Autoantibodies -- Periodicals; Autoimmune Diseases -- Periodicals; Auto-immunité -- Périodiques; Maladies auto-immunes -- Périodiques; Electronic journals; 616.978005
• DOI: 10.1016/j.jaut.2018.12.002
• Languages: English
• ISSNs: 0896-8411

Abstract

Abstract: CTLA-4 is required for CD4 + Foxp3 + regulatory T (Treg) cell function, but its mode of action remains incompletely defined. Herein we generated Ctla-4 ex2fl/fl Foxp3-Cre mice with Treg cells exclusively expressing a naturally occurring, ligand-independent isoform of CTLA-4 (liCTLA-4) that cannot interact with the costimulatory molecules CD80 and CD86. The mice did not exhibit any signs of effector T cell activation early in life, however, at 6 months of age they exhibited excessive T cell activation and inflammation in lungs. In contrast, mice with Treg cells completely lacking CTLA-4 developed lymphoproliferative disease characterized by multi-organ inflammation early in life. In vitro, Treg cells exclusively expressing liCTLA-4 inhibited CD80 and CD86 expression on dendritic cells (DC). Conversely, Treg cells required the extra-cellular part of CTLA-4 to up-regulate expression of the co-inhibitory molecule PD-L2 on DCs. Transcriptomic analysis of suppressed DCs revealed that Treg cells induced a specific immunosuppressive program in DCs. Highlights: The cell-extrinsic functions of CTLA-4 are dispensable for regulating CD80/86 expression on DCs. Regulatory T cells use CTLA-4 to induce the co-inhibitory molecule PD-L2 on dendritic cells. Regulatory T cells induce a specific genetic program in suppressed dendritic cells. CTLA-4 is required to restrict the size of the regulatory T cell pool.