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

References

• Organization GWH. WHO Treatment Guidelines for Drug-Resistant Tuberculosis, 2016 Update. 2016.
   Google Scholar
• Chung-Delgado K, Guillen-Bravo S, Revilla-Montag A, et al. Mortality among MDR-TB cases: comparison with drug-susceptible tuberculosis and associated factors. PLoS One. 2015;10(3):e0119332. doi:10.1371/journal.pone.0119332
   PubMed Web of Science ®Google Scholar
• Kilinç G, Saris A, Ottenhoff THM, et al. Host-directed therapy to combat mycobacterial infections. Immunol Rev 2021;301(1):62–83. doi:10.1111/imr.12951
   PubMed Web of Science ®Google Scholar
• Young C, Walzl G, Plessis ND. Therapeutic host-directed strategies to improve outcome in tuberculosis. Mucosal Immunol 2020;13(2):190–204. doi:10.1038/s41385-019-0226-5
   PubMed Web of Science ®Google Scholar
• Shen Y, Zhou D, Qiu L, et al. Adaptive immune response of Vgamma2Vdelta2+ T cells during mycobacterial infections. Science. 2002;295(5563):2255–2258. doi:10.1126/science.1068819
   PubMed Web of Science ®Google Scholar
• Qaqish A, Huang D, Chen CY, et al. Adoptive transfer of phosphoantigen-specific γδ T cell subset attenuates Mycobacterium tuberculosis infection in nonhuman primates. J Immunol 2017;198(12):4753–4763. doi:10.4049/jimmunol.1602019
   PubMed Web of Science ®Google Scholar
• Chen CY, Yao S, Huang D, et al. Phosphoantigen/IL2 expansion and differentiation of Vγ2Vδ2 T cells increase resistance to tuberculosis in nonhuman primates. PLoS Pathog. 2013;9(8):e1003501. doi:10.1371/journal.ppat.1003501
   PubMed Web of Science ®Google Scholar
• Chen CY, Huang D, Yao S, et al. IL-2 simultaneously expands Foxp3+ T regulatory and T effector cells and confers resistance to severe tuberculosis (TB): implicative Treg-T effector cooperation in immunity to TB. J Immunol 2012;188(9):4278–4288. doi:10.4049/jimmunol.1101291
   PubMed Web of Science ®Google Scholar
• Meraviglia S, Eberl M, Vermijlen D, et al. In vivo manipulation of Vγ9Vδ2 T cells with zoledronate and low-dose interleukin-2 for immunotherapy of advanced breast cancer patients. Clin Exp Immunol 2010;161(2):290–297. doi:10.1111/j.1365-2249.2010.04167.x
   PubMed Web of Science ®Google Scholar
• Yang E, Yang R, Guo M, et al. Multidrug-resistant tuberculosis (MDR-TB) strain infection in macaques results in high bacilli burdens in airways, driving broad innate/adaptive immune responses. Emerg Microbes Infect 2018;7(1):207.
   PubMed Web of Science ®Google Scholar
• Wang F, Shao L, Fan X, et al. Evolution and transmission patterns of extensively drug-resistant tuberculosis in China. Antimicrob Agents Chemother 2015;59(2):818–825. doi:10.1128/AAC.03504-14
   PubMed Web of Science ®Google Scholar
• Johnson JL, Ssekasanvu E, Okwera A, et al. Randomized trial of adjunctive interleukin-2 in adults with pulmonary tuberculosis. Am J Respir Crit Care Med 2003;168(2):185–191. doi:10.1164/rccm.200211-1359OC
   PubMed Web of Science ®Google Scholar
• Lin PL, Maiello P, Gideon HP, et al. PET CT identifies reactivation risk in cynomolgus macaques with latent M. tuberculosis. PLoS Pathog 2016;12(7):e1005739. doi:10.1371/journal.ppat.1005739
   PubMed Web of Science ®Google Scholar
• Ryan-Payseur B, Frencher J, Shen L, et al. Multieffector-functional immune responses of HMBPP-specific Vγ2Vδ2 T cells in nonhuman primates inoculated with Listeria monocytogenes ΔactA prfA*. J Immunol 2012;189(3):1285–1293. doi:10.4049/jimmunol.1200641
   PubMed Web of Science ®Google Scholar
• Chen CY, Huang D, Wang RC, et al. A critical role for CD8 T cells in a nonhuman primate model of tuberculosis. PLoS Pathog 2009;5(4):e1000392. doi:10.1371/journal.ppat.1000392
   PubMed Web of Science ®Google Scholar
• Shen H, Wang Y, Chen CY, et al. Th17-related cytokines contribute to recall-like expansion/effector function of HMBPP-specific Vγ2Vδ2 T cells after Mycobacterium tuberculosis infection or vaccination. Eur J Immunol 2015;45(2):442–451. doi:10.1002/eji.201444635
   PubMed Web of Science ®Google Scholar
• Yang R, Yao L, Shen L, et al. IL-12 expands and differentiates human Vγ2Vδ2 T effector cells producing antimicrobial cytokines and inhibiting intracellular mycobacterial growth. Front Immunol 2019;10(913):1–13.
   PubMedGoogle Scholar
• Yang R, Yang E, Shen L, et al. IL-12+IL-18 cosignaling in human macrophages and lung epithelial cells activates cathelicidin and autophagy, inhibiting intracellular mycobacterial growth. J Immunol 2018;200(7):2405–2417. doi:10.4049/jimmunol.1701073
   PubMed Web of Science ®Google Scholar
• Yang R, Peng Y, Pi J, et al. A CD4+CD161+ T-cell subset present in unexposed humans, Not Tb patients, are fast acting cells that inhibit the growth of intracellular mycobacteria involving CD161 pathway, perforin, and IFN-γ/autophagy. Front Immunol 2021;12:599641. doi:10.3389/fimmu.2021.599641
   PubMed Web of Science ®Google Scholar
• Shen H, Gu J, Liang S, et al. Selective destruction of IL-23 induced expansion of major antigen-specific γδ T-cell subset in TB patients. J Infect Dis 2017;215(3):420–430.
   PubMed Web of Science ®Google Scholar
• Yao S, Huang D, Chen CY, et al. CD4+ t cells contain early extrapulmonary tuberculosis (TB) dissemination and rapid TB progression and sustain multieffector functions of CD8+ T and CD3- lymphocytes: mechanisms of CD4+ T cell immunity. J Immunol 2014;192(5):2120–2132. doi:10.4049/jimmunol.1301373
   PubMed Web of Science ®Google Scholar
• Shen L, Frencher J, Huang D, et al. Immunization of Vγ2Vδ2 T cells programs sustained effector memory responses that control tuberculosis in nonhuman primates. Proc Natl Acad Sci U S A. 2019;116(13):6371–6378. doi:10.1073/pnas.1811380116
   PubMed Web of Science ®Google Scholar
• Wang F, Huang G, Shen L, et al. Genetics and functional mechanisms of STAT3 polymorphisms in human tuberculosis. Front Cell Infect Microbiol 2021;11:669394. doi:10.3389/fcimb.2021.669394
   PubMed Web of Science ®Google Scholar
• Huang D, Chen CY, Ali Z, et al. Antigen-specific Vgamma2Vdelta2 T effector cells confer homeostatic protection against pneumonic plaque lesions. Proc Natl Acad Sci U S A. 2009;106(18):7553–7558. doi:10.1073/pnas.0811250106
   PubMed Web of Science ®Google Scholar
• Shen L, Huang D, Qaqish A, et al. Fast-acting γδ T-cell subpopulation and protective immunity against infections. Immunol Rev 2020;298(1):254–263. doi:10.1111/imr.12927
   PubMed Web of Science ®Google Scholar
• Brandes M, Willimann K, Bioley G, et al. Cross-presenting human γδ T cells induce robust CD8+ αβ T cell responses. Proc Natl Acad Sci U S A. 2009;106(7):2307–2312. doi:10.1073/pnas.0810059106
   PubMed Web of Science ®Google Scholar
• Zorn E, Nelson EA, Mohseni M, et al. IL-2 regulates FOXP3 expression in human CD4+CD25+ regulatory T cells through a STAT-dependent mechanism and induces the expansion of these cells in vivo. Blood 2006;108(5):1571–1579. doi:10.1182/blood-2006-02-004747
   PubMed Web of Science ®Google Scholar
• Boyman O, Sprent J. The role of interleukin-2 during homeostasis and activation of the immune system. Nat Rev Immunol 2012;12:180–190. doi:10.1038/nri3156
   PubMed Web of Science ®Google Scholar
• Sarhan D, Leijonhufvud C, Murray S, et al. Zoledronic acid inhibits NFAT and IL-2 signaling pathways in regulatory T cells and diminishes their suppressive function in patients with metastatic cancer. Oncoimmunology 2017;6(8):e1338238. doi:10.1080/2162402X.2017.1338238
   PubMed Web of Science ®Google Scholar
• Triplett TA, Curti BD, Bonafede PR, et al. Defining a functionally distinct subset of human memory CD4+ T cells that are CD25POS and FOXP3NEG. Eur J Immunol 2012;42(7):1893–1905. doi:10.1002/eji.201242444
   PubMed Web of Science ®Google Scholar
• Seedat UF, Seedat F. Post-primary pulmonary TB haemoptysis – when there is more than meets the eye. Respir Med Case Rep. 2018;25:96–99.
   PubMed Web of Science ®Google Scholar
• Lin PL, Dietrich J, Tan E, et al. The multistage vaccine H56 boosts the effects of BCG to protect cynomolgus macaques against active tuberculosis and reactivation of latent Mycobacterium tuberculosis infection. J Clin Invest 2012;122(1):303–314. doi:10.1172/JCI46252
   PubMed Web of Science ®Google Scholar
• Liu X, Li F, Niu H, et al. IL-2 Restores T-cell dysfunction induced by persistent Mycobacterium tuberculosis antigen stimulation. Front Immunol 2019;10:2350. doi:10.3389/fimmu.2019.02350
   PubMed Web of Science ®Google Scholar
• Zhang R, Xi X, Wang C, et al. Therapeutic effects of recombinant human interleukin 2 as adjunctive immunotherapy against tuberculosis: a systematic review and meta-analysis. PLoS One 2018;13(7):e0201025. doi:10.1371/journal.pone.0201025
   PubMed Web of Science ®Google Scholar
• Cardona P, Cardona P-J. Regulatory T cells in Mycobacterium tuberculosis infection. Front Immunol 2019;10(2139):1–11.
   PubMedGoogle Scholar
• Kauffman KD, Sallin MA, Sakai S, et al. Defective positioning in granulomas but not lung-homing limits CD4 T-cell interactions with Mycobacterium tuberculosis-infected macrophages in rhesus macaques. Mucosal Immunol 2018;11(2):462–473. doi:10.1038/mi.2017.60
   PubMed Web of Science ®Google Scholar
• Sharan R, Singh DK, Rengarajan J, et al. Characterizing early T cell responses in nonhuman primate model of tuberculosis. Front Immunol 2021;12(706723):1–9.
   Google Scholar
• Seedat UF, Seedat F. Post-primary pulmonary TB haemoptysis – when there is more than meets the eye. Respir Med Case Rep 2018;25:96–99.
   PubMed Web of Science ®Google Scholar