Adoptive Transfer Of Phosphoantigen- Specific Gamma Delta T Cell Subset Attenuates Mycobacterium Tuberculosis Infection In Nonhuman Primates

The dominant V gamma 2V delta 2 T cell subset recognizes phosphoantigen and exists only in humans and nonhuman primates. Despite the discovery of gamma delta T cells >30 y ago, a proof-of-concept study has not been done to prove the principle that the V gamma 2V delta 2 T cell subset is protective against Mycobacterium tuberculosis and other infections. In this study, we used an adoptive cell-transfer strategy to define the protective role of V gamma 2V delta 2 T cells in a primate tuberculosis (TB) model. V gamma 2V delta 2 T cells for adoptive transfer displayed central/effector memory and mounted effector functions, including the production of anti-M. tuberculosis cytokines and inhibition of intracellular mycobacteria. They also expressed CXCR3/CCR5/LFA-1 trafficking/tissue-resident phenotypes and consistently trafficked to the airway, where they remained detectable from 6 h through 7 d after adoptive transfer. Interestingly, the test group of macaques receiving transfer of V gamma 2V delta 2 T cells at weeks 1 and 3 after high-dose (500 CFU) M. tuberculosis infection exhibited significantly lower levels of M. tuberculosis infection burdens in lung lobes and extrapulmonary organs than did the control groups receiving PBLs or saline. Consistently, adoptive transfer of V gamma 2V delta 2 T cells attenuated TB pathology and contained lesions primarily in the infection site of the right caudal lung lobe, with no or reduced TB dissemination to other lobes, spleen, or liver/kidney; in contrast, the controls showed widespread TB dissemination. The proof-of-concept finding supports the view that the dominant V gamma 2V delta 2 T cell subset may be included in the rational design of a TB vaccine or host-directed therapy.