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.
|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|
|Shen, Hongbo; Wang, Yunqi; Chen, Crystal Y et al. (2015) Th17-related cytokines contribute to recall-like expansion/effector function of HMBPP-specific VÎ³2VÎ´2 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 Î³Î´, 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 VÎ³2VÎ´2 T cells. J Leukoc Biol 96:957-67|
|Yao, Shuyu; Huang, Dan; Chen, Crystal Y et al. (2014) 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 192:2120-32|
|Chen, Zheng W (2013) Multifunctional immune responses of HMBPP-specific VÎ³2VÎ´2 T cells in M. tuberculosis and other infections. Cell Mol Immunol 10:58-64|
|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 VÎ³2VÎ´2 T cells increase resistance to tuberculosis in nonhuman primates. PLoS Pathog 9:e1003501|
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