HLA-E Presents Glycopeptides from the Mycobacterium tuberculosis Protein MPT32 to Human CD8+ T cells

Melanie J Harriff,David M Lewinsohn,Deborah A Lewinsohn,Elizabeth T Canfield,Wei Li,Katelynne Gardner Toren,Mary Jackson,Lisa M Wolfe,Meghan E Cansler,Todd Vogt,Gwendolyn Swarbrick,Megan Null,Karen M Dobos

doi:10.1038/s41598-017-04894-0

Melanie J Harriff, David M Lewinsohn + Show 11 more

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https://doi.org/10.1038/s41598-017-04894-0

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Infection with Mycobacterium tuberculosis (Mtb), the bacterium that causes tuberculosis, remains a global health concern. Both classically and non-classically restricted cytotoxic CD8+ T cells are important to the control of Mtb infection. We and others have demonstrated that the non-classical MHC I molecule HLA-E can present pathogen-derived peptides to CD8+ T cells. In this manuscript, we identified the antigen recognized by an HLA-E-restricted CD8+ T cell clone isolated from an Mtb latently infected individual as a peptide from the Mtb protein, MPT32. Recognition by the CD8+ T cell clone required N-terminal O-linked mannosylation of MPT32 by a mannosyltransferase encoded by the Rv1002c gene. This is the first description of a post-translationally modified Mtb-derived protein antigen presented in the context of an HLA-E specific CD8+ T cell immune response. The identification of an immune response that targets a unique mycobacterial modification is novel and may have practical impact in the development of vaccines and diagnostics.

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Tuberculosis (TB), caused by infection with Mycobacterium tuberculosis (Mtb), remains a leading cause of infectious disease morbidity and mortality worldwide, with 10.4 million new cases, including nearly 500,000 multidrug-resistant (MDR-TB) cases, and 1.8 million deaths in 2015 according to the 2016 Global Tuberculosis Report (World Health Organization)
Proteomic characterization of Mtb subcellular fractions recognized by a human HLA-E restricted T cell clone, D160 1-23
To identify potential HLA-E specific antigens, subcellular fractions generated from Mtb whole cell lysate and the culture filtrate were tested against D160 1–23 in IFN-γ ELISPOT assays

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Introduction

Tuberculosis (TB), caused by infection with Mycobacterium tuberculosis (Mtb), remains a leading cause of infectious disease morbidity and mortality worldwide, with 10.4 million new cases, including nearly 500,000 multidrug-resistant (MDR-TB) cases, and 1.8 million deaths in 2015 according to the 2016 Global Tuberculosis Report (World Health Organization). Non-classical Class I molecules, on the other hand, have limited polymorphism and present pathogen modified antigens or altered self-ligands in the context of infection. The human CD8+ T cell response to Mtb infection has been shown to involve antigen presented on both classical and non-classical Class I molecules. Recent studies analyzing T cell responses to predicted Mtb HLA-E epitopes demonstrate that HLA-E restricted CD8+ T cells can have a Th2 phenotype[17, 18] These studies underscore the potential importance of HLA-E in the response to Mtb. The limited polymorphism of HLA-E and lack of down-regulation during HIV infection makes the continued identification of Mtb-specific HLA-E antigens an attractive goal in developing novel vaccine candidates or diagnostic targets. This is the first description of a glycopeptide ligand associated with HLA-E, and has implications with regard to identification of additional pathogen-relevant HLA-E ligands

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