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

Ling Shen, James Frencher, Dan Huang, Wandang Wang, Enzhuo Yang, Crystal Y. Chen, Zhuoran Zhang, Richard Wang, Arwa Qaqish, Michelle H. Larsen, Hongbo Shen, Steven A. Porcelli, William R. Jacobs, Zheng W. Chen

Research output: Contribution to journalArticle

8 Scopus citations

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 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 fastacting 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.

Original languageEnglish (US)
Pages (from-to)6371-6378
Number of pages8
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number13
DOIs
StatePublished - Jan 1 2019

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Keywords

  • HMBPP
  • Phosphoantigen
  • Tuberculosis
  • Vaccine
  • γδ T cells

ASJC Scopus subject areas

  • General

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