Foxp3⁺ natural regulatory T cells preferentially form aggregates on dendritic cells in vitro and actively inhibit their maturation

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 105; no. 29; pp. 10113 - 10118
• Main Authors: Onishi, Yasushi, Fehervari, Zoltan, Yamaguchi, Tomoyuki, Sakaguchi, Shimon
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 22.07.2008; National Acad Sciences
• Subjects: Animals; Antigens; Antigens, CD - genetics; Antigens, CD - immunology; Antigens, CD - metabolism; B7-1 Antigen - metabolism; B7-2 Antigen - metabolism; Biological Sciences; Cell aggregates; Cell Aggregation; Cell Differentiation; Cells; Coculture techniques; CTLA-4 Antigen; Cultured cells; Delta cells; Dendritic cells; Dendritic Cells - cytology; Dendritic Cells - immunology; Dendritic Cells - metabolism; Down regulation; Female; Forkhead Transcription Factors - metabolism; Immunity; Immunology; Leukocytes; Lymphocyte Function-Associated Antigen-1 - genetics; Lymphocyte Function-Associated Antigen-1 - immunology; Lymphocyte Function-Associated Antigen-1 - metabolism; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Models, Immunological; Ova; Ovalbumin - genetics; Ovalbumin - immunology; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - metabolism; T cell receptors; T lymphocytes; T-Lymphocytes, Regulatory - cytology; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0711106105

Naturally occurring CD4⁺CD25⁺ regulatory T cells (Treg) suppress in vitro the proliferation of other T cells in a cell-contact-dependent manner. Dendritic cells (DCs) appear to be a target of Treg-mediated immune suppression. We show here that, in coculture of dye-labeled Treg cells and CD4⁺CD25⁻ naïve T cells in the presence of T cell receptor stimulation, Treg cells, which are more mobile than naïve T cells in vitro, out-compete the latter in aggregating around DCs. Deficiency or blockade of leukocyte function-associated antigen-1 (LFA-1) (CD11a/CD18) abrogates Treg aggregation, whereas that of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) (CD152) does not. After forming aggregates, Treg cells specifically down-regulate the expression of CD80/86, but not CD40 or class II MHC, on DCs in both a CTLA-4- and LFA-1-dependent manner. Notably, Treg exerts this CD80/86-down-modulating effect even in the presence of strong DC-maturating stimuli, such as GM-CSF, TNF-α, IFN-γ, type I IFN, and lipopolysaccharide. Taken together, as a possible mechanism of in vitro Treg-mediated cell contact-dependent suppression, we propose that antigen-activated Treg cells exert suppression by two distinct steps: initial LFA-1-dependent formation of Treg aggregates on immature DCs and subsequent LFA-1- and CTLA-4-dependent active down-modulation of CD80/86 expression on DCs. Both steps prevent antigen-reactive naïve T cells from being activated by antigen-presenting DCs, resulting in specific immune suppression and tolerance.