Quantitative impact of thymic selection on Foxp3 ⁺ and Foxp3 ^- subsets of self-peptide/MHC class II-specific CD4 ⁺ T cells

It is currently thought that T cells with specificity for self-peptide/ MHC (pMHC) ligands are deleted during thymic development, thereby preventing autoimmunity. In the case of CD4 ⁺ T cells, what is unclear is the extent to which self-peptide/MHC class II (pMHCII)-specific T cells are deleted or become Foxp3 ⁺ regulatory T cells. We addressed this issue by characterizing a natural polyclonal pMHCII-specific CD4 ⁺ T-cell population in mice that either lacked or expressed the relevant antigen in a ubiquitous pattern. Mice expressing the antigen contained one-third the number of pMHCII-specific T cells as mice lacking the antigen, and the remaining cells exhibited low TCR avidity. In mice lacking the antigen, the pMHCII-specific T-cell population was dominated by phenotypically naive Foxp3 ^- cells, but also contained a subset of Foxp3 ⁺ regulatory cells. Both Foxp3 ^- and Foxp3 ⁺ pMHCII-specific T-cell numbers were reduced in mice expressing the antigen, but the Foxp3 ⁺ subset was more resistant to changes in number and TCR repertoire. Therefore, thymic selection of self-pMHCII-specific CD4 ⁺ T cells results in incomplete deletion within the normal polyclonal repertoire, especially among regulatory T cells.