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J Autoimmun. 2019 Mar;98:86-94. doi: 10.1016/j.jaut.2018.12.002. Epub 2019 Jan 5.

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

Author information

1
Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
2
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
3
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
4
Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden. Electronic address: john.andersson@ki.se.

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-4ex2fl/flFoxp3-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.

KEYWORDS:

CTLA-4; Costimulation; Dendritic cells; PD-L2; Regulatory T cells

PMID:
30616979
DOI:
10.1016/j.jaut.2018.12.002

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