TNF-alpha is a positive regulatory factor for human Vgamma2 Vdelta2 T cells

Vgamma2 Vdelta2 T cells in human peripheral blood recognize phosphoantigen and play important roles in host defense and immunoregulation. The TCR is required for Vgamma2 Vdelta2 T cell responses to phosphoantigen, but less is known about soluble or cell-associated costimulatory molecules. In this study, we show that human Vgamma2 Vdelta2 T cell responses to phosphoantigen, including activation, proliferation, cytokine production, and tumor cell cytotoxicity, require TNF-alpha binding to its receptor, with a preference for TNFR2. Because stimulated Vgamma2 Vdelta2 cells also produce TNF-alpha, this may be a positive control mechanism to sustain the response. Impaired proliferation in the presence of TNF-alpha or TNFR blocking agents was partially rescued by a TLR2 agonist, Pam(3)Cys. Our studies demonstrate that TNF-alpha plays a critical role in regulating human Vgamma2 Vdelta2 T cell immune responses.