Tumor necrosis factor-alpha production is differently regulated in gamma delta and alpha beta human T lymphocytes

Tumor necrosis factor-alpha (TNF-alpha) plays a crucial role in the early d efense against pathogens. This cytokine is produced by several cell types i ncluding T lymphocytes expressing the alpha beta as well as the gamma delta T cell receptor (TcR), In human, the circulating gamma delta T cells, whic h mostly express V gamma 9V delta 2 TcR, have been strongly suggested to pl ay an important protective role against infectious agents. These activated cells early produce high amounts of TNF-alpha, which induce a determinant b eneficial effect against development of intracellular pathogens; however, s ustained production of this cytokine can result in immunopathological disea ses. 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 produc tion was shown to necessitate engagement of the TcR and CD28, and to be ind ependent of the p38 mitogen activated protein kinase pathway. We demonstrat e 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 hi ghly dependent on TcR-induced p38 kinase and extracellular signal-regulated kinase 2 pathway activation for optimal cytokine release. Moreover, we bri ng elements supporting the idea that the "activation threshold" of gamma de lta T cells leading to cytokine production is lower than that of alpha beta T cells.