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-Mediated Suppression by CD4+CD25+ T Cells Is Facilitated by CTLA-4 Signaling
* Mucosal Immunity Section, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and
Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
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-
produced by CD4+CD25+ T cells was an effector molecule mediating suppressor function. We now support this finding by imaging surface TGF- on Foxp3+CD4+CD25+ T cells in confocal fluorescence microscopy. Then, using a TGF--sensitive mink lung epithelial cell (luciferase) reporter system, we show that surface TGF- can be activated to signal upon cell-cell contact. Moreover, if such TGF- signaling is blocked in an in vitro assay of CD4+CD25+ T cell suppression by a specific inhibitor of TGF-RI, 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-. 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- at the cell-bead contact site. This suggests that CTLA-4 signaling facilitates TGF--mediated suppression by intensifying the TGF- signal at the point of suppressor cell-target cell interaction.
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