Transcription factor achaete-scute homologue 2 initiates follicular T-helper-cell development

In immune responses, activated T cells migrate to B-cell follicles and develop into follicular T-helper (T_FH) cells, a recently identified subset of CD4⁺ T cells specialized in providing help to B lymphocytes in the induction of germinal centres. Although Bcl6 has been shown to be essential in T_FH-cell function, it may not regulate the initial migration of Tcells or the induction of the T_FH program, as exemplified by C-X-C chemokine receptor type 5 (CXCR5) upregulation⁴. Here we show that expression of achaete-scute homologue 2 (Ascl2)-a basic helix-loop-helix (bHLH) transcription factor-is selectively upregulated in T FH cells. Ectopic expression of Ascl2 upregulates CXCR5 but not Bcl6, and downregulates C-C chemokine receptor 7 (CCR7) expression in T cells in vitro, as well as accelerating T-cell migration to the follicles and T_FH-cell development in vivo in mice. Genome-wide analysis indicates that Ascl2 directly regulates T FH-related genes whereas it inhibits expression of T-helper cell 1 (T_H1) and T_H17 signature genes. Acute deletion of Ascl2, as well as blockade of its function with the Id3 protein in CD4⁺ T cells, results in impaired T FH-cell development and germinal centre response. Conversely, mutation of Id3, known to cause antibody-mediated autoimmunity, greatly enhances T_FH-cell generation. Thus, Ascl2 directly initiates T FH-cell development.