Production of TNF-alpha by human V gamma 9V delta 2 T cells via engagementof Fc gamma RIIIA, 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 s ubpopulation found in blood. The majority of these cells express V gamma 9V delta2 determinants and respond to nonpeptidic phosphoantigens. Several st udies have shown that, in vivo, the percentage of V gamma 9V delta2 T cells dramatically increases during pathological infection, leading to the hypot hesis that they play an important role in the defense against pathogens. Ho wever, the specific mechanisms involved in this response remain poorly unde rstood. It has been established that V gamma 9V delta2 T cells display pote nt cytotoxic activity against virus-infected and tumor cells, thereby resem bling NK cells. In this study, we show that, upon stimulation by nonpeptidi c 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 activat ion Ag for V gamma 9V delta2 T cells. Indeed, ligation of CD16 on V gamma 9 V 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 pro tein kinases, can be modulated by CD94 NK receptors. Therefore, it appears that V gamma 9V delta2 T cells can be physiologically activated by two sequ ential steps via two different cell surface Ags: the TCR-CD3 complex and th e Fc gamma RIIIA receptor, which are specific cell surface Ags for T lympho cytes and NK cells, respectively. This strongly suggests that, in the gener al scheme of the immune response. V gamma 9V delta2 T cells represent an im portant subpopulation of cells that play a key role in the defense against invading pathogens.