Immunization of Vγ2Vδ2 T cells programs sustained effector memory responses that control tuberculosis in nonhuman primates
| العنوان: | Immunization of Vγ2Vδ2 T cells programs sustained effector memory responses that control tuberculosis in nonhuman primates |
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| المؤلفون: | William R. Jacobs, James Frencher, Zheng W. Chen, Dan Huang, Arwa Qaqish, Steven A. Porcelli, Wandang Wang, Hongbo Shen, Richard Wang, Zhuoran Zhang, Crystal Y. Chen, Enzhuo Yang, Ling Shen, Michelle H. Larsen |
| المصدر: | Proceedings of the National Academy of Sciences of the United States of America |
| بيانات النشر: | National Academy of Sciences, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | 0301 basic medicine, Male, CD8-Positive T-Lymphocytes, Lymphocyte Activation, 0302 clinical medicine, T-Lymphocyte Subsets, vaccine, Medicine, Tuberculosis Vaccines, Lung, Multidisciplinary, biology, Effector, Receptors, Antigen, T-Cell, gamma-delta, Biological Sciences, Organophosphates, 3. Good health, Vaccination, medicine.anatomical_structure, PNAS Plus, Female, HMBPP, Peptide Termination Factors, Tuberculosis, T cell, Vaccines, Attenuated, Microbiology, γδ T cells, Mycobacterium tuberculosis, 03 medical and health sciences, Interferon-gamma, phosphoantigen, Bacterial Proteins, Animals, business.industry, Membrane Proteins, biology.organism_classification, medicine.disease, Listeria monocytogenes, Macaca mulatta, Disease Models, Animal, 030104 developmental biology, Perforin, Immunization, Immunology, biology.protein, business, Immunologic Memory, CD8, 030215 immunology |
| الوصف: | Significance Despite the urgent need for a better tuberculosis (TB) vaccine, relevant protective mechanisms remain unknown. We previously defined protective phosphoantigen (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP)–specific Vγ2Vδ2 T cells as a unique subset in primates, and, here, we immunized them selectively for protection against TB. A single respiratory vaccination of macaques with attenuated HMBPP-producing Listeria monocytogenes (Lm ΔactA prfA*), but not an HMBPP-lacking ΔgcpE Listeria strain, expanded Vγ2Vδ2 T cells, elicited Th1-like Vγ2Vδ2 T cell responses, and reduced TB infection/pathology after moderate-dose TB challenge. Such protection correlated with rapid memory-like, Th1-like Vγ2Vδ2 T cell responses, the presence of tissue-resident Vγ2Vδ2 T effectors coproducing IFN-γ/perforin and inhibiting intracellular Mycobacterium tuberculosis growth, and enhanced CD4+/CD8+ T cell responses. These findings establish a concept incorporating immunization of human Vγ2Vδ2 T cells for TB vaccine development. 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 against Mycobacterium 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 attenuated Listeria monocytogenes (Lm ΔactA 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 Lm ΔgcpE strain, which did not produce HMBPP. Lm ΔactA 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. |
| اللغة: | English |
| تدمد: | 1091-6490 0027-8424 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::eb9a8daf77e9b96b21c20c1ee866198d http://europepmc.org/articles/PMC6442559 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....eb9a8daf77e9b96b21c20c1ee866198d |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10916490 00278424 |
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