The role of self-peptides in the formation and shaping of the CD4+CD25+ regulatory T cell repertoire

A clear understanding of the formation of the CD4+CD25+ regulatory T cell repertoire in the thymus and as a result of expansion in the periphery has not yet been achieved. The work presented herein examines CD4+CD25+ regulatory T cell production in a series of double transgenic mice in which CD4+ T cells bearing a transgenic T cell receptor become CD25+ when they develop in the presence of nominal antigen. CD4+CD25+ T cells are produced in five different double transgenic lineages, and in each case, increases in the number of these cells are found regardless of the deletional environment. Furthermore, in some of lineages, deletion of clonotype+ CD4+CD8+ thymocytes can be detected whereas expression of the regulatory T cell marker Foxp3 is not yet apparent. The contributions of individual stromal cell types in regulatory T cell formation and deletion is also discussed. The studies presented here do not support a model in which regulatory T cell precursors form as a result of stochastic events that bestow the ability to resist deletion when confronted with nominal antigen during development. Also presented are studies that examine the specificity requirements of CD4+CD25+ regulatory T cell selection and peripheral expansion. The data presented suggest that regulatory T cell selection may require high affinity interactions with efficiently presented self-peptides. Similarly, contact with high affinity self-peptide:MHC complexes drives the expansion of CD4+CD25+ regulatory T cells in the periphery. Yet, the data imply that the requirements for activation of suppressor function are less strict since stimulation with an analog peptide could induce CD4+CD25+ regulatory T cell-mediated suppression, but only at high concentrations of analog peptide. In all, these studies suggest that the CD4+CD25+ regulatory T cell repertoire is intentionally formed to be highly specific for and targeted to the self-antigens that are efficiently presented in the periphery