Project Description Tuberculosis (TB) remains one of the major causes of global mortality/morbidity, and has become increasingly prevalent and deadly as a result of HIV/AIDS and the emergence of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB). Global control of TB appears difficult because of the lack of an effective protective vaccine and lack of sterilizing drugs. Since drug resistance is likely to increase, there is a pressed need to develop effective vaccine or immunotherapeutic. We have recently made serial novel observations suggesting that V?2V?2 T cells, the dominant ?? T-cell subset in humans/primates, play a role in host response and immune regulation, and contribute to anti-microbial immunity against infections including M. tuberculosis (Mtb). Particularly, we elucidate that Mtb phosphoantigen (E)-4- hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) can associate with APC surface molecule, bind to TCR on V?2V?2 T cells, and activate/expand V?2V?2 T cells. Importantly, HMBPP plus IL-2 treatment of macaques induces massive expansion of multi-functional V?2V?2 T effector cells. HMBPP-expanded V?2V?2 T effector cells can traffic to and accumulate in airway/lung, produce anti-TB cytokines IFN?/perforin/granulysin, confer anti-TB immunity after Mtb infection and even induce homeostatic protection against fulminating pneumonic plague lesions in lungs. Based on these findings, we hypothesize that V?2V?2 T cells can function as anti-TB effectors, homeostatic mediators and immune regulators enhancing CD4/CD8 T-cell responses, and confer anti-TB immunity in Mtb infection. To test this hypothesis, we will I. Determine mechanisms by which HMBPP-expanded V?2V?2 T effector cells confer anti- TB immunity. II. Determine whether V?2V?2 T-cell-targeted treatments during chronic Mtb infection can confer immunotherapeutics against severe TB lesions and/or TB cavities. III. Determine if HMBPP/IL-2 expansion of V?2V?2 T cells can overcome depressed responses of CD4/CD8 T cells and protect against HIV-related TB in SHIV-infected macaques with low CD4 counts.
We propose this project based on our novel observations that a major ?? T cell subpopulation termed V?2V?2 T cells, which exist only in humans and nonhuman primates, play a role in immune responses/regulation and immunity against tuberculosis or other infectious diseases. The project will test the possibility that treatment of macaques with small molecule compound HMBPP from M. tuberculosis can expand V?2V?2 T effector cells, and induce immunity against chronic tuberculosis lesions or cavities and HIV-related tuberculosis (TB). Data may present the first in vivo evidence for immune functions of human V?2V?2 T cells, which has remained unknown since the discovery of human ?? T cells >20 years ago. Findings may also raise the possibility that V?2V?2 T-cell-targeted intervention can be explored to potentially synergize anti-TB antibiotics regimen as combined therapeutics against multi-drug- resistant TB and HIV-related TB in humans.
|Huang, Huichang; Qian, Xiaohua; Pan, Rong et al. (2018) 23-valent pneumococcal polysaccharide vaccine elicits hierarchical antibody and cellular responses in healthy and tuberculosis-cured elderly, and HIV-1-infected subjects. Clin Immunol 193:1-9|
|Yan, Shanshan; Shen, Hongbo; Lian, Qiaoshi et al. (2018) Deficiency of the AIM2-ASC Signal Uncovers the STING-Driven Overreactive Response of Type I IFN and Reciprocal Depression of Protective IFN-? Immunity in Mycobacterial Infection. J Immunol 200:1016-1026|
|Yang, Rui; Yang, Enzhuo; Shen, Ling et al. (2018) IL-12+IL-18 Cosignaling in Human Macrophages and Lung Epithelial Cells Activates Cathelicidin and Autophagy, Inhibiting Intracellular Mycobacterial Growth. J Immunol 200:2405-2417|
|Zhang, Zhuoran; Yang, Enzhuo; Hu, Chunmiao et al. (2017) Cell-Based High-Throughput Screening Assay Identifies 2',2'-Difluoro-2'-deoxycytidine Gemcitabine as a Potential Antipoliovirus Agent. ACS Infect Dis 3:45-53|
|Qaqish, Arwa; Huang, Dan; Chen, Crystal Y et al. (2017) Adoptive Transfer of Phosphoantigen-Specific ?? T Cell Subset Attenuates Mycobacterium tuberculosis Infection in Nonhuman Primates. J Immunol 198:4753-4763|
|Shen, Hongbo; Gu, Jin; Xiao, Heping et al. (2017) Selective Destruction of Interleukin 23-Induced Expansion of a Major Antigen-Specific ?? T-Cell Subset in Patients With Tuberculosis. J Infect Dis 215:420-430|
|Pi, Jiang; Jin, Hua; Jiang, Jinhuan et al. (2017) Single molecule force spectroscopy for in-situ probing oridonin inhibited ROS-mediated EGF-EGFR interactions in living KYSE-150 cells. Pharmacol Res 119:479-489|
|Chen, Zheng W (2016) Protective immune responses of major V?2V?2 T-cell subset in M. tuberculosis infection. Curr Opin Immunol 42:105-112|
|Shen, Hongbo; Wang, Feifei; Zeng, Gucheng et al. (2016) Bis-biguanide dihydrochloride inhibits intracellular replication of M. tuberculosis and controls infection in mice. Sci Rep 6:32725|
|Zhang, Jun-Ai; Liu, Gan-Bin; Zheng, Bi-Ying et al. (2016) Tuberculosis-sensitized monocytes sustain immune response of interleukin-37. Mol Immunol 79:14-21|
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