RESUMO
The importance of Th1/interferon (IFN)-γ-mediated responses in mycobacterial infection has been well established. However, little is known about B cell-mediated immunity during Mycobacterium tuberculosis (Mtb) infection. Interleukin (IL)-10-producing B cells (B10 cells), a subset of B regulatory cells (Bregs), are implicated in modulating the immune response. Herein, we found that B10 cells were significantly increased in patients with tuberculosis. Furthermore, mannose-capped lipoarabinomannan (ManLAM), a major surface lipoglycan component from Mtb, induced a significant increase in B10 cells, which enriched in CD5+ B1a B cells. ManLAM induced IL-10 production mainly by activating MyD88/PI3K/AKT/Ap-1 and K63-linked ubiquitination of NF-κB essential modulator/nuclear factor kappa-light-chain-enhancer of activated B cells signaling pathways in B cells via Toll-like receptor 2. IL-10 production by ManLAM-treated B cells further inhibited CD4+ Th1 polarization, leading to increased susceptibility to mycobacterial infection compared with ManLAM-treated IL-10-/- B group. Thus, we report a new immunoregulation mechanism in which Mtb ManLAM-induced B10 cells negatively regulate host anti-TB cellular immunity.
RESUMO
Search for novel specific antigens are urgently needed for the detection of tuberculosis (TB). In this study, we evaluated the diagnostic potential of a novel Mycobacterium tuberculosis (M.tb)-specific candidate antigen (Rv2645) from DNA segment region of differentiation (RD) 13 of M.tb and investigated T-cell recognition during natural infection in humans and experimental mice. Rv2645-specific IFN-γ levels were much higher in the peripheral blood mononuclear cells (PBMCs) of TB patients than that in healthy donors (HDs) (including Bacille Calmette-Guerin (BCG)-vaccinated donors). The enzyme-linked immunospot (ELISPOT) assay with Rv2645 had a high overall agreement (98.0%) with the results from the clinical T-SPOT.TB with 10-kD culture filtrate protein (CFP10) and 6-kD early secreted antigenic target (ESAT6) peptides. The combination of Rv2645 and CFP10-ESAT6 was better than the individual protein, with increased sensitivity and a similar specificity of 96.0% and 98.2%, respectively. Rv2654 also induced M.tb-specific skin-test responses in heat-inactivated M.tb H37Rv immunized mice. Epitope mapping revealed that Rv264530-44 and Rv2645136-143 may be the dominant T-cell and B-cell epitopes, respectively, of Rv2645. This is the first report demonstrating the Rv2654 is a strongly recognized T-cell antigen that is highly specific for TB and has potential as a novel cell-mediated immunity-based TB diagnostic agent.
