Major histocompatibility class I presentation of soluble antigen facilitated by Mycobacterium tuberculosis infection.

Abstract

Cell-mediated immune responses are essential for protection against many intracellular pathogens. For Mycobacterium tuberculosis (MTB), protection requires the activity of T cells that recognize antigens presented in the context of both major histocompatibility complex (MHC) class II and I molecules. Since MHC class I presentation generally requires antigen to be localized to the cytoplasmic compartment of antigen-presenting cells, it remains unclear how pathogens that reside primarily within endocytic vesicles of infected macrophages, such as MTB, can elicit specific MHC class I-restricted T cells. A mechanism is described for virulent MTB that allows soluble antigens ordinarily unable to enter the cytoplasm, such as ovalbumin, to be presented through the MHC class I pathway to T cells. The mechanism is selective for MHC class I presentation, since MTB infection inhibited MHC class II presentation of ovalbumin. The MHC class I presentation requires the tubercle bacilli to be viable, and it is dependent upon the transporter associated with antigen processing (TAP), which translocates antigenic peptides from the cytoplasm into the endoplasmic reticulum. The process is mimicked by Listeria monocytogenes and soluble listeriolysin, a pore-forming hemolysin derived from it, suggesting that virulent MTB may have evolved a comparable mechanism that allows molecules in a vacuolar compartment to enter the cytoplasmic presentation pathway for the generation of protective MHC class I-restricted T cells.Tuberculosis remains the largest cause of death from a single infectious disease, with over 7 million new cases and 2.0 million deaths each year (1). The molecular basis for pathogenesis of Mycobacterium tuberculosis (MTB) and the immunological mechanisms required for protection remain largely undefined. Many studies in experimental models have demonstrated that cell-mediated immunity is necessary for protection against tuberculosis. Cell transfer experiments have implicated both CD4+ and CD8+ T cells in protection (2), and the lymphokines interferon y and tumor necrosis factor a appear to be required (3-5). In addition, T cells restricted by major histocompatibility complex (MHC) class I or class I-like molecules are necessary for resistance to MTB infection, as mice deficient in MHC class I expression due to a targeted disruption of the j32-microglobulin gene are unable to control MTB growth and eventually succumb to infection (6).Following uptake by macrophages, soluble protein antigens and intracellular bacteria are initially localized in endocytic vesicles, where protein antigens are cleaved to peptides that associate with MHC class II molecules for presentation to CD4+ T cells. The mechanism by which MTB elicits class I-restricted T cells remains unclear, since the bacilli are thought to reside and grow primarily within these membranebound vesicles (7, 8), which generally do not generate antigenic peptides for presentation on MHC class I molecules. While there is some controversy as to whether a fraction of via...

Lipoprotein Access to MHC Class I Presentation During Infection of Murine Macrophages with Live Mycobacteria

“…Previous studies have provided evidence of a TAP-dependent pathway during mycobacterial infection. TAP-knockout mice have enhanced susceptibility to tuberculosis (28,62), and phagosomes in macrophages infected for 18 -36 h with live BCG show enhanced permeability to macromolecules (30,32). In contrast, the 19-kDa pathway identified in the present study belongs to the TAP-independent category and is novel in its dependence on acylation.…”

In Situ Expression of Cytokines and Cellular Phenotypes in the Lungs of Mice with Slowly Progressive Primary Tuberculosis

“…Mycobacteria have evolved mechanisms to evade the phagolysosomal environment and probably escape to the cytoplasm [58]. Cytotoxic CD8 cells recognize the antigens when presented with major histocompatibility complex (MHC) class I molecules [6].…”

Human CD8+ CTL Specific for the Mycobacterial Major Secreted Antigen 85A

“…Other groups have shown that heat shock fusion proteins and soluble Ags from M. tuberculosis can be presented via the MHC class I pathway (54,55). However, the means by which Ags, from a bacteria which has been shown to reside within the phagosome (a site inaccessible to the MHC class I presentation pathway) are presented to CD8 ϩ T cells is unclear (56,57).…”