Id3 expression defines anatomically and functionally distinct regulatory T cells

Abstract The Id (or inhibitor of DNA binding) proteins are small proteins that contain a helix-loop-helix domain and can heterodimerize with E-protein transcription factors. However, the Id proteins lack a DNA binding domain and act as natural dominant negatives of E-protein function. As a powerful transcriptional regulator, Id3 helps control the functional differentiation of CD8+ effector T cells and its expression is essential for regulatory T cell (TR) maintenance and function. Here we show that expression of Id3 is dynamically regulated in TR in a subset- and tissue-specific fashion. Within the TR compartment cTR (CD62LhiCD44lo) uniformly express Id3, however the eTR (CD62LloCD44hi) compartment can be further subdivided into Id3+ and Id3− eTR. Id3− eTR are found in low abundance in lymphoid tissues but are the majority of TR found in non-lymphoid tissue such as the skin and fat. These Id3− eTR express higher levels of inhibitory surface markers and have similar molecular profiles to the recently described ST2+ tissue TR. We propose that Id3 maintains a lymphoid-tissue TR phenotype and loss of Id3 promotes localization and retention of TR in non-lymphoid tissue.