Transcription factor Achaete-Scute homologue 2 initiates T follicular helper cell development

In immune responses, activated T cells migrate to B cell follicles and develop to T follicular helper (Tfh) cells, a new subset of CD4(+) T cells specialized in providing help to B lymphocytes in the induction of germinal centers (1,2). Although Bcl6 has been shown to be essential in Tfh cell function, it may not regulate the initial migration of T cells (3) or the induction of Tfh program as exampled by C-X-C chemokine receptor type 5 (CXCR5) upregulation (4). Here, we show that Achaete-Scute homologue 2 (Ascl2), a basic helix-loop-helix (bHLH) transcription factor (5), is selectively upregulated in its expression in Tfh cells. Ectopic expression of Ascl2 upregulates CXCR5 but not Bcl6 and downregulates C-C chemokine receptor 7 (CCR7) expression in T cells in vitro and accelerates T cell migration to the follicles and Tfh cell development in vivo. Genome-wide analysis indicates that Ascl2 directly regulates Tfh-related genes while inhibits expression of Th1 and Th17 genes. Acute deletion of Ascl2 as well as blockade of its function with the Id3 protein in CD4(+) T cells results in impaired Tfh cell development and the germinal center response. Conversely, mutation of Id3, known to cause antibody-mediated autoimmunity, greatly enhances Tfh cell generation. Thus, Ascl2 directly initiates Tfh cell development.