Control of regulatory T cell and T(h)17 cell differentiation by inhibitory helix-loop-helix protein Id3

The molecular mechanisms directing Foxp3 gene transcription in CD4(+) T cells remain ill defined. We show that deletion of the inhibitory helix-loop-helix (HLH) protein Id3 results in defective Foxp3(+) T(reg) cell generation. We identified two transforming grothw factor-β1 (TGF-β1)-dependent mechanisms that are vital for activation of Foxp3 gene transcription, and are defective in Id3(−/−) CD4(+) T cells. Enhanced binding of the HLH protein E2A to the Foxp3 promoter promoted Foxp3 gene transcription. Id3 was required to relieve inhibition by GATA-3 at the Foxp3 promoter. Further, Id3(−/−) T cells increased differentiation of T(h)17 cells in vitro and in a mouse asthma model. A network of factors therefore act in a TGF-β-dependent manner to control Foxp3 expression and inhibit T(h)17 cell development.