Regulatory T cell lineage commitment in the thymus

A substantial fraction of the Foxp3+ CD4+ regulatory T (Treg) cell repertoire is generated through instructive and/or selective processes in the thymus, and there is some consensus that clonal deviation into the Treg lineage is a result of self-antigen recognition. Paradoxically, the same holds true for a diametrically different cell fate decision of developing thymocytes, namely their removal from the repertoire through apoptotic cell death (clonal deletion). Here, we will review our current understanding of how T cell receptor stimulation, cytokine signaling, co-stimulation, epigenetic modifications and T cell intrinsic developmental tuning synergize during Treg cell differentiation, and how instructive signals converge at the Foxp3 gene-locus during entry into the Treg cell lineage. We will also discuss how these parameters relate to known determinants of negative selection.