Loss of Cellular Immune Response against Shared Mycobacterial Antigens is Associated with Active Pulmonary Tuberculosis in Adults

Background: Devising strategies for prevention of pulmonary tuberculosis is critical to halt onward transmission of tuberculosis. Since BCG has been shown to be ineffective in preventing pulmonary tuberculosis, studies for determining protective mechanisms are warranted for effective vaccine designing. We conducted a study in latently infected healthy individuals and healthy contacts of pulmonary tuberculosis for understanding protective immune responses against adult pulmonary tuberculosis caused by reactivation and re-infection, respectively.Methods: We enrolled healthy latently infected individuals (LTB, n=22), household contacts (HCTB, n=16) of pulmonary tuberculosis patients and sputum positive pulmonary TB patients (ATB, n=19). Latent infection was determined by IFN-γ release assay against ESAT-6 and CFP-10. Cytokines secreted against shared and M. tuberculosis specific antigens were determined by IFN-γ ELISPOT and multiplex assays. Mycobacteria specific T cells were identified using MHC-I restricted ESAT-6 and Ag85B tetramers. Expression of different chemokine receptors associated with Th1 and Th17 responses was determined by flow cytometry.Results: LTB group showed highest IFN-γ response and significantly higher response against 38 kDa and Ag85C than ATB group. IFN-γ responses against ESAT-6 correlated negatively with those against 38 kDa in HCTB group (r=-0.51, p=0.021). Levels of IL-17A, IL-17F and IL-6 were highest in HCTB group against 38 kDa. ATB group showed significantly lower ratios of Ag85B to ESAT-6 tetramer positive CD8+ T cells as compared to LTB group. ATB patients had lower frequencies of T cells expressing CCR5 and CCR6 than LTB and HCTB groups, respectively, indicating loss of Th1 and Th17 immune responses.Conclusion: The study suggested a role of Th1 and Th17 responses in mediating protection against reactivation versus re-infection type of adult pulmonary TB, respectively. It also highlighted importance of shared mycobacterial antigens like 38 kDa and Ag85 in mediating these protective responses indicating their role in effective TB vaccine designing.