**9.6 Regulatory T cells**

Regulatory T cells (Tregs), also called suppressor T cells, suppress the activation of clonespecific T-cell activity. Tregs account for 10-15% of CD4+ T cells and express the transmembrane protein CD25, which is the alpha chain of the IL-2 receptor. CD4+CD25+ Tregs are anergic to TCR-mediated activation but potently suppress the activation of other T cells. However, not all CD25+ T cells are regulators. Some naive T cells upregulate CD25 in response to antigen, a change that represents the activation rather than the suppression of an immune response. The thymus produces anergic but suppressive CD4+ 25+ T cells, which are also identified by the expression of FoxP3, the transcription factor responsible for their development. These T cells suppress the activation and expansion of autoreactive CD4+CD25- populations.

Studies in mice have shown that Tregs are antigen-specific and that they regulate peripheral tolerance by producing suppressive cytokines such as IL-10 and TGF-beta. They depend on continuous antigen exposure to stay capable of mediating suppression. Antigen removal reduces the quantity of cells.

In allograft rejection, direct stimulation of T cells in response to donor-derived antigens presented by donor APCs had been the focus of transplantation research for many years. However, indirect antigen presentation, in which self-APCs present donor peptides in an MHC-restricted fashion is responsible for the induction of antigen-specific Tregs that can directly and indirectly suppress other alloreactive T cells. Although positive costimulation with CD28 appears to be necessary for the development of intrathymically derived Tregs, costimulation blockade with CTLA-4 is required for the development of peripherally acquired suppressor Tregs.
