Peptide Specificity of Thymic Selection of CD4+CD25+ T Cells

Abstract

The CD4+CD25+ regulatory T cells can be found in the thymus, but their need to undergo positive and negative selection has been questioned. Instead, it has been hypothesized that CD4+CD25+ cells mature following TCR binding to MHC backbone, to low abundant MHC/peptide complexes, or to class II MHC loaded with peripheral autoantigens. In all these circumstances, processes that are distinct from positive and negative selection would govern the provenance of CD4+CD25+ cells in the thymus. By comparing the development of CD4+CD25− and CD4+CD25+ cells in mice expressing class II MHC molecules bound with one or many peptide(s), we show that the CD4+CD25+ cells appear during natural selection of CD4+ T cells. The proportion of CD4+CD25+ cells in the population of CD4+ thymocytes remains constant, and their total number reflects the complexity of selecting class II MHC/peptide complexes. Hence, thymic development of CD4+CD25+ cells does not exclusively depend on the low-density, high-affinity MHC/peptide complexes or thymic presentation of peripheral self-Ags, but, rather, these cells are selected as a portion of the natural repertoire of CD4+ T cells. Furthermore, while resistant to deletion mediated by endogenous superantigen(s), these cells were negatively selected on class II MHC/peptide complexes. We postulate that while the CD4+CD25+ thymocytes are first detectable in the thymic medulla, their functional commitment occurs in the thymic cortex.