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(1,2). Although Bcl6 has been shown to be essential in T-FH-cell function, it may not regulate the initial migration of T cells(3) or the induction of the T-FH program, as exemplified by C-X-C chemokine receptor type 5 (CXCR5) upregulation(4). Here we show that expression of achaete-scute homologue 2 (Ascl2)-a basic helix-loop-helix (bHLH) transcription factor(5)-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(H)1) and T(H)17 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.