Adjunctive Zoledronate + IL-2 administrations enhance anti-tuberculosis Vγ2Vδ2 T-effector populations, and improve treatment outcome of multidrug-resistant tuberculosis¹

ABSTRACT

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 Vγ2Vδ2 T cells play protective roles in immunity against TB. Here, we hypothesized that enhancing protective Vγ2Vδ2 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 Vγ2Vδ2 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 Vγ2Vδ2 T cells and enhanced/sustained Vγ2Vδ2 T-effector subpopulation producing anti-TB cytokines until week 21. ZOL/IL-2 administrations, while expanding Vγ2Vδ2 T cells, significantly increased/sustained numbers of circulating CD4⁺ Th1 and CD8⁺ Th1-like effector populations, with some γδ T- or αβ 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 Vγ2Vδ2 T- and αβ T-effector populations, and improve treatment outcome of MDR-TB.

KEYWORDS:

• Multidrug-resistant tuberculosis
• adjunctive immunotherapy
• Vγ2Vδ2 T cells
• nonhuman primates
• Zoledronate
• IL-2

Acknowledgements

Studies were supported by Shanghai Science and Technology Committee Basic Research Grant [No. 20JC1417800 and 20ZR1446900 to HS, 20ZR1406200 to FW, shslczdzc03001 to WS], Chinese National Major Projects Grants [2018ZX10731301-006-001 to HS], National Natural Science Foundation of China Grants [31970876 and 32070943 to HS], and supported by the Fundamental Research Funds for the Central Universities [22120210563 to HS]. We thank Dr. Dan Huang for joining LS for pathology studies as well as Dr Zheng W Chen for this project’s design, sharing of protocols/assays, and data evaluation/discussion/interpretation using his overtimes at night before May 2019. LS is the PI in both the AbbVie and the PBL research grants.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

Studies were supported by Shanghai Science and Technology Committee Basic Research Grant [grant number 20JC1417800 and 20ZR1446900 to HS, 20ZR1406200 to FW, shslczdzc03001 to WS], Chinese National Major Projects Grants [2018ZX10731301-006-001 to HS], National Natural Science Foundation of China Grants [31970876 and 32070943 to HS], and supported by the Fundamental Research Funds for the Central Universities [22120210563 to HS].