TGF-beta-Mediated Suppression by CD4+CD25+ T Cells Is Facilitated by CTLA-4 Signaling

• Published in: The Journal of immunology (1950) Vol. 177; no. 4; pp. 2331 - 2339
• Main Authors: Oida, Takatoku, Xu, LiLi, Weiner, Howard L, Kitani, Atsushi, Strober, Warren
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 15.08.2006
• Subjects: Animals; Antigens, CD; Antigens, Differentiation - physiology; Cell Line; CTLA-4 Antigen; Immune Tolerance; Mice; Mice, Inbred A; Signal Transduction - immunology; T-Lymphocytes, Regulatory - immunology; Transforming Growth Factor beta - biosynthesis; Transforming Growth Factor beta - physiology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.177.4.2331

CD4+CD25+ T cells play a pivotal role in immunological homeostasis by their capacity to exert immunosuppressive activity. However, the mechanism by which these cells function is still a subject for debate. We previously reported that surface (membrane) TGF-beta produced by CD4+CD25+ T cells was an effector molecule mediating suppressor function. We now support this finding by imaging surface TGF-beta on Foxp3+CD4+CD25+ T cells in confocal fluorescence microscopy. Then, using a TGF-beta-sensitive mink lung epithelial cell (luciferase) reporter system, we show that surface TGF-beta can be activated to signal upon cell-cell contact. Moreover, if such TGF-beta signaling is blocked in an in vitro assay of CD4+CD25+ T cell suppression by a specific inhibitor of TGF-betaRI, suppressor function is also blocked. Finally, we address the role of CTLA-4 in CD4+CD25+ T cell suppression, showing first that whereas anti-CTLA-4 does not block in vitro suppressor function, it does complement the blocking activity of anti-TGF-beta. We then show with confocal fluorescence microscopy that incubation of CD4+CD25+ T cells with anti-CTLA-4- and rB7-1/Fc-coated beads results in accumulation of TGF-beta at the cell-bead contact site. This suggests that CTLA-4 signaling facilitates TGF-beta-mediated suppression by intensifying the TGF-beta signal at the point of suppressor cell-target cell interaction.