Tumor necrosis factor-α production is differently regulated in γδ and αβ human T lymphocytes

Abstract

Tumor necrosis factor-α (TNF-α) plays a crucial role in the early defense against pathogens. This cytokine is produced by several cell types including T lymphocytes expressing the αβ as well as the γδ T cell receptor (TcR). In human, the circulating γδ T cells, which mostly express Vγ9Vδ2 TcR, have been strongly suggested to play an important protective role against infectious agents. These activated cells early produce high amounts of TNF-α, 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-α production in Vγ9Vδ2 T cells are totally unknown. In primary αβ T cells, TNF-α 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 αβ T cells, TNF-α production in Vγ9Vδ2 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 γδ T cells leading to cytokine production is lower than that of αβ T cells.