Increased numbers and suppressive activity of regulatory CD25+CD4+ T lymphocytes in the absence of CD4 engagement by MHC class II molecules

• CD4+ Treg develop in transgenic mice expressing mutant MHC II incapable of binding to CD4.
• Relative numbers of CD25+CD4+ Treg are increased.
• Activated Treg suppress IL-2 secretion in normally selected CD4+ T cells.
• Treg suppression is contact-dependent.

Mechanisms of central and peripheral tolerance prevent autoimmunity. Regulatory T cells inhibit the activation of potentially auto-reactive T cells in peripheral lymphoid organs. In transgenic mice in which all MHC class II molecules are incapable of binding to CD4, class II MHC-restricted T cells preferentially differentiated into immunosuppressive, regulatory T cells. In these mutant MHC class II transgenic mice, a subset of CD4+ T cells constitutively expressed moderately elevated levels of CD25 and potently inhibited interleukin-2 secretion by T cells from normal mice in a cell-to-cell, contact-dependent manner. Immunosuppressive activity depended on activation of the regulatory T cells. Thus, CD25+CD4+ T cells from mutant MHC class II transgenic mice resembled phenotypically and functionally a major subset of natural regulatory T cells in normal mice, but were two to three-times more abundant. These results further clarify the mechanisms that govern the differentiation and maintenance of CD25+CD4+ regulatory T cells, and present avenues for immunomodulation.