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Division of Immunity and Infection, Medical Research Council Centre for Immune Regulation, Institute of Biomedical Research, University of Birmingham Medical School, Birmingham, United Kingdom
The role of CTLA-4 in regulatory T cell (Treg) function is not well understood. We have examined the role of CTLA-4 and its relationship with the transcription factor FoxP3 using a model of Treg induction in human peripheral blood. Activation of human CD4+CD25– T cells resulted in the appearance of a de novo population of FoxP3-expressing cells within 48 h. These cells expressed high levels of CTLA-4 and cell sorting on expression of CTLA-4 strongly enriched for FoxP3+-expressing cells with suppressive function. Culture in IL-2 alone also generated cells with suppressive capacity that also correlated with the appearance of CTLA-4. To directly test the role of CTLA-4, we transfected resting human T cells with CTLA-4 and found that this method conferred suppression, similar to that of natural Tregs, even though these cells did not express FoxP3. Furthermore, transfection of FoxP3 did not induce CTLA-4 and these cells were not suppressive. By separating the expression of CTLA-4 and FoxP3, our data show that FoxP3 expression alone is insufficient to up-regulate CTLA-4; however, activation of CD4+CD25– T cells can induce both FoxP3 and CTLA-4 in a subpopulation of T cells that are capable of suppression. These data suggest that the acquisition of suppressive behavior by activated CD4+CD25– T cells requires the expression of CTLA-4, a feature that appears to be facilitated by, but is not dependent on, expression of FoxP3.
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1 This work was supported by the Biotechnology and Biological Sciences Research Council and the Medical Research Council (Y.Z.), by the Wellcome Trust (C.N.M.), and by the Biotechnology and Biological Sciences Research Council (O.Q.). L.S.K.W. is an Medical Research Council Career Development Fellow.
2 Address correspondence and reprint requests to Dr. David M. Sansom, Division of Immunity and Infection, Medical Research Council Centre for Immune Regulation, Vincent Drive, Birmingham B15 2TT, U.K. E-mail address: D.M.Sansom{at}bham.ac.uk
3 Abbreviations used in this paper: Treg, regulatory T cell; DC, dendritic cell; PPD, purified protein derivative.
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