IL-21 Regulates the Differentiation of a Human γδ T Cell Subset Equipped with B Cell Helper Activity

V gamma 9V delta 2 T lymphocytes recognize nonpeptidic antigens without presentation by MHC molecules and display pleiotropic features. Here we report that coculture of V gamma 9V delta 2 cells with phosphoantigen and IL-21 leads to selective expression of the transcription repressor Bcl-6 and polarization toward a lymphocyte subset displaying features of follicular B-helper T (TFH) cells. T-FH-like V gamma 9V delta 2 cells have a predominant central memory (CD27(+)CD45RA(-)) phenotype and express ICOS, CD40L and CXCR5. Upon antigen activation, they secrete IL-4, IL-10 and CXCL13, and provide B-cell help for antibody production in vitro. Our findings delineate a subset of human V gamma 9V delta 2 lymphocytes, which, upon interaction with IL-21-producing CD4 TFH cells and B cells in secondary lymphoid organs, is implicated in the production of high affinity antibodies against microbial pathogens.