TGF-β Control of Adaptive Immune Tolerance: A Break From Treg Cells

The vertebrate adaptive immune system has well defined functions in maintaining tolerance to self-tissues. Suppression of autoreactive T cells is dependent on the regulatory cytokine transforming growth factor-beta (TGF-beta) and regulatory T (Treg) cells, a distinct T cell lineage specified by the transcription factor Foxp3. Although TGF-beta promotes thymic Treg (tTreg) cell development by repressing T cell clonal deletion and peripheral Treg cell differentiation by inducing Foxp3 expression, a recent study shows that TGF-beta suppresses autoreactive T cells independent of Foxp3(+) Treg cells. These findings imply that as an ancestral growth factor family member, TGF-beta may have been co-opted as a T cell-intrinsic mechanism of self-tolerance control to assist the evolutionary transition of vertebrate adaptive immunity. Later, perhaps in placental mammals upon their acquisition of a TGF-beta regulatory element in the Foxp3 locus, the TGF-beta pathway is further engaged to induce peripheral Treg cell differentiation and expand the scope of T cell tolerance control to innocuous foreign antigens.