HMBPP-deficient Listeria mutant immunization alters pulmonary/systemic responses, effector functions, and memory polarization of V gamma 2V delta 2 T cells

Role for microbial production of phosphoantigen in infection-driven responses of primate gamma delta T cells in vivo. Whereas infection or immunization of humans/primates with microbes coproducing HMBPP/IPP can remarkably activate V gamma 2V delta 2 T cells, in vivo studies have not been done to dissect HMBPP- and IPP-driven expansion, pulmonary trafficking, effector functions, and memory polarization of V gamma 2V delta 2 T cells. We define these phosphoantigen-host interplays by comparative immunizations of macaques with the HMBPP/IPP-coproducing Listeria Delta actA prfA* and HMBPP-deficient Listeria Delta actA Delta gcpE prfA* mutant. The HMBPP-deficient Delta gcpE mutant shows lower ability to expand V gamma 2V delta 2 T cells in vitro than the parental HMBPP-producing strain but displays comparably attenuated infectivity or immunogenicity. Respiratory immunization of macaques with the HMBPP-deficient mutant elicits lower pulmonary and systemic responses of V gamma 2V delta 2 T cells compared with the HMBPP-producing vaccine strain. Interestingly, HMBPP-deficient mutant reimmunization or boosting elicits enhanced responses of V gamma 2V delta 2 T cells, but the magnitude is lower than that by HMBPP-producing listeria. HMBPP-deficient listeria differentiated fewer V gamma 2V delta 2 T effector cells capable of coproducing IFN- gamma and TNF- alpha and inhibiting intracellular listeria than HMBPP-producing listeria. Furthermore, HMBPP deficiency in listerial immunization influences memory polarization of V gamma 2V delta 2 T cells. Thus, both HMBPP and IPP production in listerial immunization or infection elicit systemic/pulmonary responses and differentiation of V gamma 2V delta 2 T cells, but a role for HMBPP is more dominant. Findings may help devise immune intervention.