Mycobacterium tuberculosis (M.tb)-induced tuberculosis (TB) remains the leading morbidity and mortality worldwide, and the magnitude of the problem continues to grow, due in part to HIV pandemics. Sustained increases in cases of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) strains are making TB extremely difficult to treat and globally control. Since drug resistance is likely to increase, there is a pressed need to develop new vaccines or immunotherapeutics. We have recently shown that IL-2 treatment of macaques can induce remarkable expansion of CD4+CD25(high)Foxp3+ T regulatory cells (Treg) in systemic and respiratory sites, and more importantly confers apparent homeostatic protection against TB lesions. This surprising finding suggests that Treg can function in vivo as homeostatic regulator against TB, far beyond simple inhibition of immune responses. Based on this novel observation, we hypothesize that IL-2-expanded Treg can orchestrate or balance host responses and suppress M.tb-mediated inflammatory events, leading to no or mild TB lesions, whereas IL-2-activated T effector cells producing IFN?;or cytotoxic cytokine may help to limit M.tb replication and dissemination. To test this hypothesis, we will: I. Perform mechanistic studies to determine a critical role of IL-2-expanded Foxp3+ Treg in anti-TB immunity in macaques. II. Determine if intermittent IL-2 treatments during chronic active M.tb infection can sustain Treg expansion, down-regulate TB-driven inflammatory events or associated M.tb replication, and confer immunotherapeutics against severe TB lesions and/or TB cavities. III. Examine kinetics and function of Treg during SHIV-induced reactivation of latent M.tb co-infection, and determine if combined ART and intermittent IL-2 treatment can expand Treg and ?d, CD8 T effector cells, and confer immunotherapeutics against AIDS-related reactivation TB.
This project is proposed based on our recent novel observation that cytokine IL-2 treatment of macaques induces remarkable expansion of CD4+Foxp3+ T regulatory cells (Treg), and confers apparent protection against tuberculosis disease or tissue damages. Studies will elucidate immune mechanisms for IL-2-induced anti-tuberculosis immunity, and explore IL-2-based treatment modalities for tuberculosis and AIDS-related tuberculosis. Findings will exert sustained, long-term impact on tuberculosis research and provide potential alternative treatment for tuberculosis, multi-drug resistant tuberculosis, and AIDS-related tuberculosis.
|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, Crystal Y; Yao, Shuyu; Huang, Dan et al. (2013) Phosphoantigen/IL2 expansion and differentiation of Výý2Výý2 T cells increase resistance to tuberculosis in nonhuman primates. PLoS Pathog 9:e1003501|
|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|
|Frencher, James T; Ryan-Pasyeur, Bridgett K; Huang, Dan et al. (2013) SHIV antigen immunization alters patterns of immune responses to SHIV/malaria coinfection and protects against life-threatening SHIV-related malaria. J Infect Dis 208:260-70|
|Chen, Zheng W (2013) Multifunctional immune responses of HMBPP-specific V?2V?2 T cells in M. tuberculosis and other infections. Cell Mol Immunol 10:58-64|
|Chen, Crystal Y; Huang, Dan; Yao, Shuyu et al. (2012) 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 188:4278-88|
|Huang, Dan; Chen, Crystal Y; Zhang, Meihong et al. (2012) Clonal immune responses of Mycobacterium-specific ýýýý T cells in tuberculous and non-tuberculous tissues during M. tuberculosis infection. PLoS One 7:e30631|
|Chen, Zheng W (2011) Immune biology of Ag-specific ýýýý T cells in infections. Cell Mol Life Sci 68:2409-17|
|Ryan-Payseur, Bridgett; Ali, Zahida; Huang, Dan et al. (2011) Virus infection stages and distinct Th1 or Th17/Th22 T-cell responses in malaria/SHIV coinfection correlate with different outcomes of disease. J Infect Dis 204:1450-62|
|Qiu, Jin; Yan, Lin; Chen, Jianbo et al. (2011) Intranasal vaccination with the recombinant Listeria monocytogenes ýýactA prfA* mutant elicits robust systemic and pulmonary cellular responses and secretory mucosal IgA. Clin Vaccine Immunol 18:640-6|
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