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
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Shen, Hongbo; Wang, Yunqi; Chen, Crystal Y et al. (2015) 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 45:442-51
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
Zeng, Jincheng; Song, Zeqing; Cai, Xiaozhen et al. (2015) Tuberculous pleurisy drives marked effector responses of γδ, CD4+, and CD8+ T cell subpopulations in humans. J Leukoc Biol 98:851-7
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Zhong, Liyun; Zhang, Zhun; Lu, Xiaoxu et al. (2013) NSOM/QD-based visualization of GM1 serving as platforms for TCR/CD3 mediated T-cell activation. Biomed Res Int 2013:276498
Wang, Hui; Cai, Huai-Hong; Zhang, Lu et al. (2013) A novel gold nanoparticle-doped polyaniline nanofibers-based cytosensor confers simple and efficient evaluation of T-cell activation. Biosens Bioelectron 50:167-73
Chen, Crystal Y; Yao, Shuyu; Huang, Dan et al. (2013) Phosphoantigen/IL2 expansion and differentiation of Vγ2Vδ2 T cells increase resistance to tuberculosis in nonhuman primates. PLoS Pathog 9:e1003501

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