Differentiation of naïve T cells into Tfh cells is directed by the transcription factor B cell lymphoma 6 (Bcl-6). Bcl-6, a transcriptional repressor, suppresses expression or activity of the transcription factors T-bet, GATA3 and ROR gamma t, which drive the development of other helper T cell subsets, Th1, Th2, and Th17, respectively. Bcl-6 also indirectly induces the expression of accessory proteins important for Tfh localization and function, including CXCR5 and PD-1, by repressing several clusters of microRNAs that negatively regulate these molecules. Additionally, Bcl-6 induces expression of B and T lymphocyte attenuator (BTLA), CD200 and the receptors for IL-6 and IL-21.
Recent investigation into the molecular mechanisms underlying Tfh differentiation revealed two signaling pathways that drive Bcl-6 expression. Activation of the IL-6 receptor on Tfh cells stimulates the transcription factor STAT3. Interaction of ICOS on Tfh cells with the ICOS ligand on B cells induces the c-Maf transcription factor. Both STAT3 and c-Maf drives IL-21 expression. The autocrine action of IL-21 induces Bcl-6 expression. Bcl-6 is suppressed by the B-lymphocyte induced maturation protein 1 (BLIMP1). R&D Systems offers products to aid in the investigation of the transcriptional regulation of Tfh cell differentiation.