Immunization of Vγ2Vδ2 T cells programs sustained effector memory responses that control tuberculosis in nonhuman primates

Abstract

Tuberculosis (TB) remains a leading killer among infectious diseases, and a better TB vaccine is urgently needed. The critical components and mechanisms of vaccine-induced protection againstMycobacterium tuberculosis(Mtb) remain incompletely defined. Our previous studies demonstrate that Vγ2Vδ2 T cells specific for (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) phosphoantigen are unique in primates as multifunctional effectors of immune protection against TB infection. Here, we selectively immunized Vγ2Vδ2 T cells and assessed the effect on infection in a rhesus TB model. A single respiratory vaccination of macaques with an HMBPP-producing attenuatedListeria monocytogenes(LmΔactA prfA*) caused prolonged expansion of HMBPP-specific Vγ2Vδ2 T cells in circulating and pulmonary compartments. This did not occur in animals similarly immunized with an LmΔgcpEstrain, which did not produce HMBPP. LmΔactA prfA* vaccination elicited increases in Th1-like Vγ2Vδ2 T cells in the airway, and induced containment of TB infection after pulmonary challenge. The selective immunization of Vγ2Vδ2 T cells reduced lung pathology and mycobacterial dissemination to extrapulmonary organs. Vaccine effects coincided with the fast-acting memory-like response of Th1-like Vγ2Vδ2 T cells and tissue-resident Vγ2Vδ2 effector T cells that produced both IFN-γ and perforin and inhibited intracellular Mtb growth. Furthermore, selective immunization of Vγ2Vδ2 T cells enabled CD4+and CD8+T cells to mount earlier pulmonary Th1 responses to TB challenge. Our findings show that selective immunization of Vγ2Vδ2 T cells can elicit fast-acting and durable memory-like responses that amplify responses of other T cell subsets, and provide an approach to creating more effective TB vaccines.

γδ T‐cell responses during HIV infection and antiretroviral therapy

“…Only a single study has reported BAL cd T-cell numbers in healthy and HIV-infected participants where there was a significant increase in total cd cells during HIV infection, but the delta chain usage was not determined. 93 NHP studies will be critical in determining whether host-directed therapy targeting Vd2 T cells 94 95 These cells are suggested to participate in the control of CMV replication and display potent anti-CMV responses in vitro. Na€ ıve macaques are able to induce robust primary and recall Vd2 responses to BCG vaccination in the periphery and lung, while SIV-infected macaques showed no response to BCG in either site.…”

“…92 Encouragingly, administration of ART improved NHP Vd2 responses to BCG, possibly due to reconstitution of Mtb-specific CD4 + T cells. 93 NHP studies will be critical in determining whether host-directed therapy targeting Vd2 T cells 94 can enhance protection against TB reactivation in HIV-infected populations.…”

Control of Mycobacterium tuberculosis Infection in Lungs is Associated with Recruitment of Antigen-Specific Th1 and Th17 cells Co-expressing CXCR3 and CCR6

“…Thus, defining immune responses associated with establishing and maintaining human LTBI remains challenging. NHPs, e.g., macaques, recapitulate multiple aspects of human Mtb infection and disease progression and are attractive animal models for studying LTBI (16, 33-38). We recently showed that rhesus macaques with asymptomatic Mtb infection harbor viable Mtb bacteria in their lungs for up to nine months(20).…”

Macrophage‐Targeted Isoniazid–Selenium Nanoparticles Promote Antimicrobial Immunity and Synergize Bactericidal Destruction of Tuberculosis Bacilli

“…We combined our decade‐long nanotechnology and TB immunology expertise to innovate the macrophage‐targeted selenium nanomaterials for synergistic antimicrobial and bactericidal destruction of Mtb in host cells. Virtually, selenium nanomaterials can function as anticancer agents, inhibit E. coli , S .…”