Abstract
Follicular helper T cells (Tfh) have been identified as the primary cell subpopulation regulating B cell responses in germinal centers, thus supporting high-affinity antibody production. Among the transcription factors orchestrating Tfh cell differentiation and function, the role played by the proto-oncogene c-Maf remains poorly characterized. We report herein that selective loss of c-Maf expression in the T cell compartment results in defective development of Tfh cells in response to both antigen/adjuvant vaccinations and commensal intestinal bacteria. Accordingly, c-Maf expression in T cells was essential for the development and high-affinity antibody secretion in vaccinated animals. c-Maf was expressed early, concomitantly to BCL6, in Tfh cell precursors and found to regulate Tfh fate in a cell-autonomous fashion. Altogether, our findings reveal a novel, non-redundant, function for c-Maf in the differentiation of Tfh cells and the regulation of humoral immune responses to T-cell-dependent antigens.
Highlights
Follicular helper T cells (Tfh) are key regulators of germinal center (GC) formation and T celldependent long-term humoral immunity
We demonstrate that c-Maf plays a major, non-redundant role in the differentiation of Tfh cells in vivo. c-Maf is expressed early during Tfh cell induction and mice harboring a T cell-specific conditional ablation of c-Maf are strongly impaired in their Tfh response to both antigen/adjuvant vaccinations and commensal intestinal bacteria
By using retroviral ectopic expression of c-Maf or BCL6 in in vitro-derived human Tfh cells, Kroenke et al first reported that c-Maf and BCL6 regulated distinct features of Tfh cell function, with BCL6 being critical for T cell positioning within the follicle and directing T–B interactions and c-Maf promoting and sustaining IL-21 secretion [10]
Summary
Follicular helper T cells (Tfh) are key regulators of germinal center (GC) formation and T celldependent long-term humoral immunity. They provide crucial signals to B lymphocytes in GCs and guide high-affinity, isotype-switched, antibody responses, and memory B cell development [1]. T lymphocytes engage in cognate interaction and ICOS-ICOSL signaling with dendritic cells (DCs) These signals promote expression of CXCR5, allowing Th cells to relocalize at the T–B border zone where they receive additional signals from B cells [5, 6]. This second wave of interactions further stabilizes Tfh cell fate—characterized by a high expression of BCL6 and surface markers such as CXCR5, PD1, ICOS—and results in the migration toward GCs and the delivery of optimal helper signals to B cells [5,6,7]
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