Interactions of Mycobacterium tuberculosis with the MHC class I antigen processing and presentation pathway
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Abstract
Experimental evidence has implicated T cells that recognize antigens in the context of classical MHC Class I and nonclassical Class I-like molecules in the protective response toward Mycobacterium tuberculosis (MTB). The aim of this work was to characterize both types of lymphocytes, and to explore the basis of communication between the tubercle bacilli and the MHC Class I pathway of the host macrophage.;Our initial objective was to isolate MHC Class I-restricted CD8{dollar}\sp{lcub}+{rcub}{dollar} T cells specific for mycobacterial antigens in vitro. Potential peptide epitopes were selected from the protein sequences of MTB antigens based on the peptide-binding motif of the HLA-A2 MHC Class I allele. Peptides with binding affinity for HLA-A2 were tested for their ability to specifically stimulate CD8{dollar}\sp{lcub}+{rcub}{dollar} T cells from mycobacteria-sensitized HLA-A2{dollar}\sp{lcub}+{rcub}{dollar} donors, and from HLA-A2 transgenic mice that had been immunized with MTB.;We have also examined the interaction of the MTB phagosome with the cytoplasmic antigen presentation pathway. A model system was developed using exogenously added ovalbumin as a surrogate antigen in MTB-infected macrophages. Virulent MTB and closely related mycobacterial species facilitated the presentation of ovalbumin on MHC Class I molecules to CD8{dollar}\sp{lcub}+{rcub}{dollar} cytotoxic T cells (CTL). MTB-stimulated presentation was dependent upon viable organisms and the cytosolic transport of peptides implying communication between the MTB phagosome and the host cell cytoplasm. MHC Class I presentation of soluble antigens was mimicked by the intracellular pathogen Listevia monocytogenes, which grows within the host cell cytoplasm, as well as its purified hemolysin.;Another aim was to characterize T cells that recognize nonpeptide MTB antigens presented by CD1 molecules. CD1-restricted CTL were shown to lyse macrophages infected with virulent MTB. CD1-restricted CTL were divided into distinct subsets based on their surface phenotype (CD4{dollar}\sp{lcub}-{rcub}{dollar}CD8{dollar}\sp{lcub}-{rcub}{dollar} versus CD8{dollar}\sp{lcub}+{rcub}{dollar}) and cytotoxicity mechanism (Fas receptor-mediated versus granule exocytosis). A functional consequence of these two mechanisms was observed that while both CTL subsets lysed MTB-infected macrophages, only those CTL utilizing the granule exocytosis pathway were able to reduce the viability of intracellular MTB.