Production of TNF-α by human Vγ9Vδ2 T cells via engagement of FcγRIIIA, the low affinity type 3 receptor for the Fc portion of IgG, expressed upon TCR activation by nonpeptidic antigen

Human lymphocytes expressing the gamma delta TCR represent a minor T cell subpopulation found in blood. The majority of these cells express V gamma 9V delta2 determinants and respond to nonpeptidic phosphoantigens. Several studies have shown that, in vivo, the percentage of V gamma 9V delta2 T cells dramatically increases during pathological infection, leading to the hypothesis that they play an important role in the defense against pathogens. However, the specific mechanisms involved in this response remain poorly understood. It has been established that V gamma 9V delta2 T cells display potent cytotoxic activity against virus-infected and tumor cells, thereby resembling NK cells. In this study, we show that, upon stimulation by nonpeptidic Ags, V gamma 9V delta2 T cells express Fc gamma RIIIA (CD16), a receptor that is constitutively expressed on NK cells. CD16 appears to be an activation Ag for V gamma 9V delta2 T cells. Indeed, ligation of CD16 on V gamma 9V delta2 T cells leads to TNF-a production. This TNF-a production, which is dependent (like that induced via the TCR-CD3 complex) on the activation of the p38 and extracellular signal- regulated kinase-2 mitogen-activated protein kinases, can be modulated by CD94 NK receptors. Therefore, it appears that V gamma 9V delta2 T cells can be physiologically activated by two sequential steps via two different cell surface Ags: the TCR-CD3 complex and the Fc gamma RIIIA receptor, which are specific cell surface Ags for T lymphocytes and NK cells, respectively. This strongly suggests that, in the general scheme of the immune response. V gamma 9V delta2 T cells represent an important subpopulation of cells that play a key role in the defense against invading pathogens.