Evasion and subversion of antigen presentation by Mycobacterium tuberculosis

Abstract

Mycobacterium tuberculosis is one of the most successful of human pathogens and has acquired the ability to establish latent or progressive infection and persist even in the presence of a fully functioning immune system. The ability of M. tuberculosis to avoid immune-mediated clearance is likely to reflect a highly evolved and coordinated program of immune evasion strategies, including some that interfere with antigen presentation to prevent or alter the quality of T-cell responses. Here, we review an extensive array of published studies supporting the view that antigen presentation pathways are targeted at many points by pathogenic mycobacteria. These studies show the multiple potential mechanisms by which M. tuberculosis may actively inhibit, subvert or otherwise modulate antigen presentation by major histocompatibility complex class I, class II and CD1 molecules. Unraveling the mechanisms by which M. tuberculosis evades or modulates antigen presentation is of critical importance for the development of more effective new vaccines based on live attenuated mycobacterial strains.

Figure 1. Disruption of MHC Class II presentation by Mycobacterium tuberculosis

The various steps in the MHC class II processing and presentation pathway that are known or postulated to be influenced by M. tuberculosis infection are illustrated. A) New synthesis of MHC class II molecules is blocked by TLR2 signaling due to mycobacterial products such as the 19-kDa lipoprotein. B) Intracellular trafficking of MHC class II is disrupted by the suppression of cathepsin S, which is due to induction of IL-10 by mycobacterial infection. C) Generation of peptide antigens for loading onto MHC class II in relevant endocytic compartments (MIIC) is also inhibited by several effects of mycobacterial infection, including inhibition of phagosome-lysosome fusion, neutralization of phagosomal pH by urease (UreC) and by blockade of recruitment of the vaculolar proton ATPase. D) A proposed inhibition of autophagy and autophagic vacuole formation also eliminates a potential source of antigenic peptides that can load MHC class II molecules. E) The reduction of peptide antigen availability and incomplete cleavage of MHC class II associated Ii resulting from cathepsin S suppression result in a reduced transport of stable peptide loaded MHC class II molecules to the APC surface.

Figure 2. MHC class I presentation pathways in Mycobacterium tuberculosis infection

The large cell on the left of the figure represents a macrophage infected with M. tuberculosis. Newly synthesized MHC class I molecules in the endoplasmic reticulum (ER) are loaded with peptides that are produce by the cytosolic proteosome complex and transported into the ER lumen by TAP. Additional trimming of the cytosol derived peptides can occur as a result of aminopeptidase activity in the ER lumen. Escape of mycobacterial proteins from the phagosome into the cytosol can lead to peptide presentation by this classical MHC class I pathway (A). Mechanisms for loading of peptides onto MHC class I molecules in the lumen of the phagosome are also likely to exist. This vacuolar pathway for cross presentation (B) may involve transfer of ER membrane components (e.g., newly synthesized MHC class I complexes and TAP) to the phagosome membrane, enabling the loading of peptides generated in the cytosol. Alternatively, peptides may be generated by proteases in the phagosome lumen, and these may be loaded by a process of peptide exchange onto MHC class I molecules recycling from the plasma membrane. The so-called “detour pathway” (C) is a third way that peptides from a vacuolar intracellular pathogen such as M. tuberculosis can be cross presented by MHC class I. In this case, an infected cell must first die by apoptosis, and the released apoptotic vesicles carry the mycobacterial antigens into uninfected dendritic cells. Current evidence suggests that all of these pathways are likely to be actively inhibited or effectively bypassed during M. tuberculosis infection (see text and Table 1 for details).