Human Vγ2Vδ2 T cells produce IFN-γ and TNF-α with an on/off/on cycling pattern in response to live bacterial products

Whereas cytokine production in alpha beta T cells is rapidly regulated by exposure to peptide Ag, the mechanisms regulating cytokine production by gamma delta T cells are unknown. In this study, we demonstrate that human V gamma 2V delta2 T cells produce IFN-gamma and TNF-alpha as early as 2 h after Ag exposure, and that they produce these cytokines in a dose- and time- dependent manner in response to stimulation with a live bacterial product, iso-butylamine (IBA), but not to dead bacteria or LPS. gamma delta T cells began, ceased, and then resumed IFN-gamma and TNF-alpha generation in an on/off/on cycling pattern, both in vitro and in vivo, depending on the presence or absence of IBA. IFN-gamma and TNF-alpha, whose optimum production was dependent on IBA-stimulated gamma delta T cells, were critical for monocyte-mediated killing of Escherichia coli. By limiting cytokine production to periods of direct contact with live bacteria, gamma delta T cells focus their resources at the site of infection, while limiting systemic immunopathology. Thus, human gamma delta T cells may mediate innate resistance to extracellular bacteria via tightly regulated cytokine production without necessarily expanding in number.