Adjunctive Zoledronate + IL-2 administrations enhance anti-tuberculosis V gamma 2V delta 2 T-effector populations, and improve treatment outcome of multidrug-resistant tuberculosis

Multidrug-resistant tuberculosis (MDR-TB) is a refractory disease with high mortality rate due to no or few choices of antibiotics. Adjunctive immunotherapy may help improve treatment outcome of MDR-TB. Our decade-long studies demonstrated that phosphoantigen-specific V gamma 2V delta 2 T cells play protective roles in immunity against TB. Here, we hypothesized that enhancing protective V gamma 2V delta 2 T-effector cells could improve treatment outcome of MDR-TB. To address this, we employed clinically approved drugs Zoledronate (ZOL) and IL-2 to induce anti-TB V gamma 2V delta 2 T-effector cells as adjunctive immunotherapy against MDR-TB infection of macaques. We found that adjunctive ZOL/IL-2 administrations during TB drugs treatment of MDR-TB-infected macaques significantly expanded V gamma 2V delta 2 T cells and enhanced/sustained V gamma 2V delta 2 T-effector subpopulation producing anti-TB cytokines until week 21. ZOL/IL-2 administrations, while expanding V gamma 2V delta 2 T cells, significantly increased/sustained numbers of circulating CD4(+) Th1 and CD8(+) Th1-like effector populations, with some gamma delta T- or alpha beta T-effector populations trafficking to airway at week 3 until week 19 or 21 after MDR-TB infection. Adjunctive ZOL/IL-2 administrations after MDR-TB infection led to lower bacterial burdens in lungs than TB drugs alone, IL-2 alone or saline controls, and resulted in milder MDR-TB pathology/lesions. Thus, adjunctive Zoledronate + IL-2 administrations can enhance anti-TB V gamma 2V delta 2 T- and alpha beta T-effector populations, and improve treatment outcome of MDR-TB.