Abstract
Background and methods Initiation of a thymus-dependent humoral immune response requires interaction of activated B cells and follicular B helper T (Tfh) cells, a specialized subset of CD4 T helper (Th) cells. Differentiation of Tfh cells leads to their localization to B cell follicles and germinal centers (GC) of secondary lymphoid organs, with their expression of costimulatory proteins and secretion of cytokines promoting GC B-cell proliferation, immunoglobulin gene hypermutation, and development of B-cell memory and long-lived plasma cells.
Results and conclusions The transcriptional repressor Bcl6 acts cell autonomously to drive a Tfh-cell development program, including upregulation of proteins necessary for function, with environmental signals promoting differentiation of these cells at the expense of other CD4 T-cell subsets. Tfh cells undergo differentiation within the GC, in part mediated by STAT4 and STAT6-driven chromatin remodeling, enabling differential cytokine production and consequent help to B cells, with affinity selection of the latter promoted by regulatory GC T cells. Therapeutically, blockade of Tfh-GC B interactions interrupts end-organ disease in the systemic autoimmune disease lupus, while resetting the Tfh-cell phenotype toward normal homeostasis.
Acknowledgements Supported by NIH AR40072 and AR068662, and the Lupus Research Alliance.
