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.

Agency
National Institute of Health (NIH)
Institute
Office of The Director, National Institutes of Health (OD)
Type
Research Project (R01)
Project #
5R01OD015092-12
Application #
8670046
Study Section
Immunity and Host Defense (IHD)
Program Officer
Harding, John D
Project Start
2013-06-03
Project End
2018-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
12
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Illinois at Chicago
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Chicago
State
IL
Country
United States
Zip Code
60612
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
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
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
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
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
Wang, Yang; Zhong, Huiling; Xie, Xiaodan et al. (2015) Long noncoding RNA derived from CD244 signaling epigenetically controls CD8+ T-cell immune responses in tuberculosis infection. Proc Natl Acad Sci U S A 112:E3883-92
Shen, Hongbo; Wang, Yunqi; Chen, Crystal Y et al. (2015) Th17-related cytokines contribute to recall-like expansion/effector function of HMBPP-specific V?2V?2 T cells after Mycobacterium tuberculosis infection or vaccination. Eur J Immunol 45:442-51
Zeng, Jincheng; Song, Zeqing; Cai, Xiaozhen et al. (2015) Tuberculous pleurisy drives marked effector responses of ??, CD4+, and CD8+ T cell subpopulations in humans. J Leukoc Biol 98:851-7
Frencher, James T; Shen, Hongbo; Yan, Lin et al. (2014) HMBPP-deficient Listeria mutant immunization alters pulmonary/systemic responses, effector functions, and memory polarization of V?2V?2 T cells. J Leukoc Biol 96:957-67

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