IL-21 enhances the potential of human γδ T cells to provide B-cell help

V?9/Vd2 T cells are a minor subset of T cells in human blood and differ from all other lymphocytes by their specific responsiveness to (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), a metabolite produced by a large range of microbial pathogens. V?9/Vd2 T cells can be skewed towards distinct effector functions, in analogy to, and beyond, the emerging plasticity of CD4+ T cells. As such, depending on the microenvironment, V?9/Vd2 T cells can assume features reminiscent of Th1, Th2, Th17 and Treg cells as well as professional APCs. We here demonstrate that V?9/Vd2 T cells express markers associated with follicular B helper T (TFH) cells when stimulated with HMB-PP in the presence of IL-21. HMB-PP induces upregulation of IL-21R on V?9/Vd2 T cells. In return, IL-21 plays a co-stimulatory role in the expression of the B-cell-attracting chemokine CXCL13, the CXCL13 receptor CXCR5 and the inducible co-stimulator by activated V?9/Vd2 T cells, and enhances their potential to support antibody production by B cells. The interaction between HMB-PP-responsive V?9/Vd2 T cells, IL-21-producing TFH cells and B cells in secondary lymphoid tissues is likely to impact on the generation of high affinity, class-switched antibodies in microbial infections.