Molecular mechanisms of regulatory T cell development and suppressive function.

ABSTRACT

The requirement for regulatory T cells (Treg) to maintain tolerance to self-tissues is evidenced by fatal autoimmune disease that results from genetic deficiencies in Treg cell development or Treg cell depletion in vivo. These observations revealed that a normal T cell repertoire harbors self-reactive T cells that are kept dormant by Treg cells. In order to prevent auto-reactive T cell activation, Treg cells disarm antigen-presenting cells (APC) through multiple suppressive mechanisms including B7 signaling and sequestration, ATP catabolism, cytolysis, and immunosuppressive cytokine secretion. In addition to APCs, multiple leukocyte subsets are subjected to Treg cell mediated suppression. The acquisition of suppressive activity occurs concomitantly with Treg cell lineage commitment. The identification of molecular cues that guide differentiation of Treg cells versus auto-reactive cells or other CD4(+) T cell subsets have been aided by the differential expression of the transcription factor Foxp3 by Treg cells. Foxp3 is the most faithful marker for Treg cells and in its absence, Treg cell development is abrogated. Utilizing Foxp3 expression as a surrogate for Treg cell commitment, factors that promote Foxp3 transcription have provided new insights to Treg cell development at a molecular level.