Becoming self-aware: The thymic education of regulatory T cells

The generation of Foxp3⁺ regulatory T (Treg) cells in the thymus is essential for immune homeostasis. In the past several years, substantial progress has been made in understanding the mechanisms by which a minor portion of developing thymocytes are selected to become Treg cells. Although previously controversial, recent data support the importance of TCR specificity as a primary determinant for selecting self-reactive thymocytes to become Treg cells in a multi-step process involving cytokines, co-stimulatory molecules, and a variety of antigen-presenting cells. Importantly, the antigenic niche for Treg cell development appears to be typically quite small, implying the recognition of tissue-specific, rather than ubiquitous, self-antigens. Finally, it appears that an NF-κB transcription factor, c-Rel, may be the link between TCR recognition and the induction of Foxp3 expression, which is required for the function and stability of the natural Treg cell population.