Id2 reinforces TH1 differentiation and inhibits E2A to repress TFH differentiation

The differentiation of helper T cells into effector subsets is critical to host protection. Transcription factors of the E-protein and Id families are important arbiters of T cell development, but their role in the differentiation of the T(H)1 and T-FH subsets of helper T cells is not well understood. Here, T(H)1 cells showed more robust Id2 expression than that of T-FH cells, and depletion of Id2 via RNA-mediated interference increased the frequency of T-FH cells. Furthermore, T(H)1 differentiation was blocked by Id2 deficiency, which led to E-protein-dependent accumulation of effector cells with mixed characteristics during viral infection and severely impaired the generation of T(H)1 cells following infection with Toxoplasma gondii. The T-FH cell-defining transcriptional repressor Bcl6 bound the Id2 locus, which provides a mechanism for the bimodal Id2 expression and reciprocal development of T(H)1 cells and T-FH cells.