Regulatory T Cell Development from the Top Down: the Role of T Cell Receptor-Generated Second Messengers in Thymic Regulatory T Cell Development

Regulatory T cells (Treg)s are a subset of CD4 + T cells with suppressive properties. Their function and development relies on the expression of the lineage-determining transcription factor Foxp3. Mutations in Foxp3 result in the failure of Treg development, leading to widespread autoimmunity and death in mice and in humans. Although some Tregs acquire expression of Foxp3 in the periphery (inducible Tregs; iTregs), a larger proportion of Tregs called natural Tregs (nTregs) are generated in the thymus during T cell development. Thymic Treg development is dependent on intracellular signal transduction events transduced by the T cell receptor (TCR), co-stimulatory molecules, and cytokines. Here we review the proximal signals emanating from the TCR that are essential for proper thymic Treg development, with particular emphasis on the PLCγ pathway.