On the elusive TCR specificity of thymic regulatory T cells

Therapies using thymus-derived regulatory T cells (Tregs) are promising strategies for preventing autoimmunity or graft rejection. The efficacy of these approaches is, however, contingent on a better understanding of Treg mode of action, especially about factors controlling their activation in vivo. Although key parameters of Treg suppression have been identified, little information is available on Treg activation in vivo via the TCR. In light of recent studies using TCR transgenic mouse models as well as unpublished data, we discuss evidence in support of the view that Treg TCR specificities are not necessarily highly diverse, that the accessibility of Treg selective antigens control Treg development, and that peptides derived from MHC class II (MHC-II) could be prevailing antigens involved in Treg selection. This novel perspective provides insights on Treg development as well as a conceptual basis to a significant contribution of MHC-II derived peptides in the shaping of the Treg TCR repertoire.