Prolonged (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate-driven antimicrobial and cytotoxic responses of pulmonary and systemic Vγ2Vδ2 T cells in macaques

Although phosphoantigen-specific V gamma 2V delta 2 T cells appear to play a role in antimicrobial and anticancer immunity, mucosal immune responses and effector functions of these gamma delta T cells during infection or phospholigand treatment remain poorly characterized. In this study, we demonstrate that the microbial phosphoantigen (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) plus IL-2 treatment of macaques induced a prolonged major expansion of circulating V gamma 2V delta 2 T cells that expressed CD8 and produced cytotoxic perforin during their peak expansion. Interestingly, HMBPP-activated V gamma 2V delta 2 T cells underwent an extraordinary pulmonary accumulation, which lasted for 3-4 mo, although circulating V gamma 2V delta 2 T cells had returned to baseline levels weeks prior. The V gamma 2V delta 2 T cells that accumulated in the lung following HMBPP/IL-2 cotreatment displayed an effector memory phenotype, as follows: CCR5(+)CCR7(-)CD45RA(-)CD27(+) and were able to re-recognize phosphoantigen and produce copious amounts of IFN-gamma up to 15 wk after treatment. Furthermore, the capacity of massively expanded V gamma 2V delta 2 T cells to produce cytokines in vivo coincided with an increase in numbers of CD4(+) and CD8(+) alpha beta T cells after HMBPP/IL-2 cotreatment as well as substantial perforin expression by CD3(+)V gamma 2(-) T cells. Thus, the prolonged HMBPP-driven antimicrobial and cytotoxic responses of pulmonary and systemic V gamma 2V delta 2 T cells may confer immunotherapeutics against infectious diseases and cancers.