Multieffector-Functional Immune Responses of HMBPP-Specific Vγ2Vδ2 T Cells in Nonhuman Primates Inoculated with Listeria monocytogenes ΔactA prfA*

Although Listeria monocytogenes can induce systemic infection causing spontaneous abortion, septicemia, and meningitis, studies have not been performed to investigate human anti-L. monocytogenes immune responses, including those of Ag-specific V gamma 2V delta 2 T cells, a dominant human gamma delta T cell subset. L. monocytogenes is the only pathogen known to possess both the mevalonate and non-mevalonate isoprenoid biosynthesis pathways that produce metabolic phosphates or phosphoantigens activating human V gamma 2V delta 2 T cells, making it interesting to explore in vivo anti-L. monocytogenes immune responses of V gamma 2V delta 2 T cells. In this study, we demonstrated that subclinical systemic L. monocytogenes infection of rhesus macaques via parenteral inoculation or vaccination with an attenuated Listeria strain induced multieffector-functional immune responses of phosphoantigen-specific V gamma 2V delta 2 T cells. Subclinical systemic infection and reinfection with attenuated L. monocytogenes uncovered the ability of V gamma 2V delta 2 T cells to mount expansion and adaptive or recall-like expansion. Expanded V gamma 2V delta 2 T cells could traffic to and accumulate in the pulmonary compartment and intestinal mucosa. Expanded V gamma 2V delta 2 T cells could evolve into effector cells producing IFN-gamma, TNF-alpha, IL-4, IL-17, or perforin after L. monocytogenes infection, and some effector V gamma 2V delta 2 T cells could coproduce IL-17 and IFN-gamma, IL-4 and IFN-gamma, or TNF-alpha and perforin. Surprisingly, in vivo-expanded V gamma 2V delta 2 T effector cells in subclinical L. monocytogenes infection could directly lyse L. monocytogenes-infected target cells and inhibit intracellular L. monocytogenes bacteria. Thus, we present the first demonstration, to our knowledge, of multieffector-functional V gamma 2V delta 2 T cell responses against L. monocytogenes. The Journal of Immunology, 2012, 189: 1285-1293.