Targeting microbial-specific gamma/delta T-cell subset for vaccine development

Abstract

Abstract Tuberculosis (TB), caused by M. tuberculosis (Mtb), remains the top killer among infectious diseases. The current TB vaccine, Bacille Calmette–Guérin (BCG), only protects young children from severe disseminated TB, but not effectively protects against pulmonary TB in adults. Improved TB vaccine or vaccination approach is needed for effective global prevention against TB. Our decade-long mechanistic studies in nonhuman primates (NHP) employed 2 innovative “gain-of-function” manipulations to generate Vγ2Vδ2 T effector cells in vivo for definition of their function and immunity against high-dose TB. These seminal studies established that HMBPP-specific Vγ2Vδ2 T effector cells are fast-acting, multi-functional and protective against high-dose TB in NHP. These novel findings prompted us to perform creative immunization of Vγ2Vδ2 T subset using our innovative vaccine vector Listeria ΔactA prfA*. Respiratory vaccination of macaques with an HMBPP-producing attenuated LM ΔactA prfA*, but not the control, caused prolonged expansion of HMBPP-specific Vγ2Vδ2 T cells in pulmonary and circulating compartments. After pulmonary Mtb challenge, macaques vaccinated with LM ΔactA prfA* exhibited rapid memory-like response of Vγ2Vδ2+ Th1 cells. The selective immunization of Vγ2Vδ2 T cells contained Mtb infection/dissemination and reduced lung TB pathology, enhancing the ability of tissue-resident Vγ2Vδ2 T cells to inhibit Mtb growth in macrophages. Thus, selective immunization of Vγ2Vδ2 T cells elicits fast-acting/durable memory-like responses, providing an approach to creating more effective TB vaccines.