Cutting Edge: Dynamic Expression of Id3 Defines the Stepwise Differentiation of Tissue-Resident Regulatory T Cells

Foxp3⁺ regulatory T (T_R) cells are phenotypically and functionally diverse and broadly distributed in lymphoid and nonlymphoid tissues. However, the pathways guiding the differentiation of tissue-resident T_R cell populations have not been well defined. By regulating E-protein function, Id3 controls the differentiation of CD8⁺ effector T cells and is essential for T_R cell maintenance and function. We show that dynamic expression of Id3 helps define three distinct mouse T_R cell populations: Id3⁺CD62L^hiCD44^lo central T_R cells, Id3⁺CD62L^loCD44^hi effector T_R (eT_R) cells, and Id3^- eT_R cells. Adoptive transfer experiments and transcriptome analyses support a stepwise model of differentiation from Id3⁺ central T_R to Id3⁺ eT_R to Id3^- eT_R cells. Furthermore, Id3^- eT_R cells have high expression of functional inhibitory markers and a transcriptional signature of tissue-resident T_R cells. Accordingly, Id3^- eT_R cells are highly enriched in nonlymphoid organs but virtually absent from blood and lymph. Thus, we propose that tissue-resident T_R cells develop in a multistep process associated with Id3 downregulation.