Functional and molecular characterization of B cell‐responsive Vδ1+ γδ T cells

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Abstract
Cells expressing the Vδ1+ gene segment are a minor γδ T cell population in human peripheral blood but predominate in epithelia and (inflamed) tissues. The characteristic dendritic‐like morphology of these γδ T cells is consistent with their putative immune surveillance role in epithelia. Their function, however, remains unknown. We and others previously reported that a subset of Vδ1+ γδ T cells proliferates after stimulation with Epstein‐Barr virus (EBV)‐transformed B lymphoblastoid cell lines (LCL), but not with fresh peripheral blood‐derived B cells. These responses were independent of the type of T cell receptor (TcR) γ chain co‐expressed with the Vδ1 chain. The in vivo relevance of this LCL‐mediated activation as well as the nature of the stimulatory ligand on the LCL is not well established. In this study, we tested the proliferative response of Vδ1+ LCL‐responsive T cells against non‐EBV‐transformed B cells, activated through CD40 by murine EL4 B5 cells, and to a panel of B cell lines differing in the expression of EBV nuclear antigen proteins and adhesion/co‐stimulatory molecules. The role of the Epstein‐Barr virus‐derived antigen in the induction of this response could be excluded as the activated (non‐EBV‐transformed) peripheral blood B cells were also able to induce a proliferative response in the LCL‐responsive Vδ1+ T cells. Therefore, the stimulatory ligand on B cells is of cellular rather than of viral origin, and its expression is up‐regulated upon activation of B cells. The expression of B7 and CD39 molecules on the surface of activated B cells appeared to be crucial since antibodies to these structures could block the induction of proliferation of the Vδ1+ T cells. Finally, we investigated the diversity of the responding Vδ1+ γδ T cell clones by sequence analysis of the TcRδ junctional regions. No restricted V‐D‐J sequences were found among the LCL‐responsive Vδ1+ T cell clones, arguing strongly against a mono‐ or oligoclonal Vδ1+ γδ T cell response to LCL. These findings may explain the presence of polyclonally activated Vδ1+ T cells in inflamed tissues where activated B cells are often present.