Dysregulation of the host mevalonate pathway during early bacterial infection activates human TCR γδ cells

Primates, but not rodents, have T cell receptor V gamma 9-V gamma 2 T cells bridging innate and adaptive antimicrobial immunity. This T cell population is activated by prenyl pyrophosphates isolated from microbial or eukaryotic cells. Although the microbial metabolites are more active than the cellular ones, their involvement in TCR gamma delta activation during infection has not been studied. Here, we show that, during the initial phases of infections with Escherichia coli and Staphylococcus aureus, TCR gamma delta cells are activated by endogenous mevalonate metabolites. infections with low bacteria inocula up-regulate the production and accumulation of host-derived TCR gamma delta stimulatory antigens within 1 h, which is followed by a peak of TCR gamma delta cell activation at 5 h. Infections induce the accumulation and dephosphorylation of the hydroxymethylglutaryl-coenzyme A reductase, the rate-limiting enzyme of the mevalonate pathway, resulting in increased activity of this enzyme and in increased synthesis of intermediate metabolites. Thus, primates have evolved the ability to readily respond to bacterial infection by sensing the dysregulation of the mevalonate pathway within infected cells, as a mechanism of immediate antimicrobial immunity.