Immune evasion by Mycobacterium tuberculosis: Mycobacterial lipoproteins exploit Toll-like receptor-2 signaling to inhibit class-II MHC antigen processing

Mycobacterium tuberculosis survives in the face of a highly active and effective adaptive immune response. Multiple mechanisms likely contribute to mycobacterial survival, but the ability to avoid detection by primed mycobacterial specific T cells would permit M. tuberculosis to hide within infected macrophages and escape eradication.; Class I and Class II MHC antigen processing are essential to initiate T cell activation as well as T cell recognition of infected macrophages. Therefore, the ability to inhibit these processes would confer a distinct advantage for intracellular M. tuberculosis. This study has demonstrated that mycobacterial lipoproteins are capable of exploiting Toll-like receptor-2 signaling in human macrophages to inhibit MHC-II antigen processing as well as activation by IFN-gamma, while still inducing the acute inflammatory response associated with TLRs. The inhibition of IFN-gamma activation was not unique to MHC-II expression and may be part of a much larger, global regulation of inflammation that inhibits constitutive MHC-II antigen processing in primary human macrophages, allowing M. tuberculosis to decrease the presentation of its antigens to CD4 T cells. Inhibition of MHC-II antigen processing and avoiding detection by CD4 T cells present the obvious advantage of escaping elimination by a protective immune response, resulting in the ability of M. tuberculosis to remain harbored within macrophages until immunological pressure subsides and reactivation of latent infection occurs.; CD8 T cells also play an important role in protection and require MHC-I antigen processing for activation. The processing of mycobacterial antigens via the MHC-I pathway has not been thoroughly studied nor has the possibility of mycobacterial inhibition of MHC-I processing. Progress was made in developing an immunization and re-stimulation protocol that resulted in 20--50% peptide specific CD8 T cells for fusion and generation of an MHC-I restricted T cell hybridoma, a valuable reagent to investigate the issues mentioned above.