Tumor necrosis factor-alpha (TNF-alpha) plays a crucial role in the early defense against pathogens. This cytokine is produced by several cell types including T lymphocytes expressing the alpha beta as well as the gamma delta T cell receptor (TcR), In human, the circulating gamma delta T cells, which mostly express V gamma 9V delta 2 TcR, have been strongly suggested to play an important protective role against infectious agents. These activated cells early produce high amounts of TNF-alpha, which induce a determinant beneficial effect against development of intracellular pathogens; however, sustained production of this cytokine can result in immunopathological diseases. The signals that regulate TNF-alpha production in V gamma 9V delta 2 T cells are totally unknown. In primary alpha beta T cells, TNF-alpha production was shown to necessitate engagement of the TcR and CD28, and to be independent of the p38 mitogen activated protein kinase pathway. We demonstrate herein that, in contrast to alpha beta T cells, TNF-alpha production in V gamma 9V delta 2 T lymphocytes is independent of CD28 costimulation and highly dependent on TcR-induced p38 kinase and extracellular signal-regulated kinase 2 pathway activation for optimal cytokine release. Moreover, we bring elements supporting the idea that the "activation threshold" of gamma delta T cells leading to cytokine production is lower than that of alpha beta T cells.
