CD94/NKG2 Inhibitory Receptor Complex Modulates Both Anti-Viral and Anti-Tumoral Responses of Polyclonal Phosphoantigen-Reactive Vγ9Vδ2 T Lymphocytes

Viral, bacterial, protozoal, and cancer-associated Ags elicit strong responses in human γδ T lymphocytes. The majority of these cells in the peripheral blood express the Vγ9Vδ2-encoded TCR and recognize nonpeptidic phosphoantigens without an apparent MHC restriction. We have shown that Vγ9Vδ2 T cells express the inhibitory CD94/NKG2 receptor for HLA class I molecules The anti-CD94 mAb inhibits 1) the Vγ9Vδ2 T cell proliferation in response mycobacterial phosphoantigens and 2) the HIV-induced Vγ9Vδ2 T cell expansion. Vγ9Vδ2 T cells stimulated with nonpeptidic mycobacterial antigens produce IFN-γ and TNF-α. Signaling through the CD94/NKG2 receptor interferes with the synthesis of these cytokines. The CD94/HLA class I interaction is also involved in the cytotoxic activity of Vγ9Vδ2 T cells. The Vγ9Vδ2 T cell regulation through the CD94 receptor may be important for the potentially dual function in innate immunity, i.e., 1) NK-like and 2) TCR ligand-induced cytolytic activities.