Tuberculosis remains an important clinical problem throughout the world. The causative agent of tuberculosis, Mycobacterium tuberculosis (Mtb), is a facultative intracellular pathogen, residing primarily in macrophages. Protective immunity to tuberculosis depends upon the coordinated response of the cellular immune system. Because CD8+ T cells recognize and destroy target cells infected with intracellular pathogens, the CD8+ T cell response may be important for containment of Mtb and elimination of infected cells. Identification and characterization of human cytotoxic T cells may be essential for the understanding of immunity to tuberculosis, and hence may be required for the development of efficacious vaccines and improved therapeutic strategies. In prior work, we have demonstrated that both classically and non-classically restricted, Mtb-specific responses are present in persons infected with Mtb, have demonstrated that CD8+ T cell preferentially recognize heavily infected DC, have demonstrated that non-classically restricted responses comprise a significant fraction of the overall response, and have demonstrated that the non-classical major histocompatibility molecule HLA-E can present Mtb-derived antigen. This work represented the first description of the use of the HLA-lb molecule HLA-E in the recognition of an intracellular pathogen. As a result, the goal of this continuing application is to further our understanding of this antigen recognition system. An increased understanding of this pathway has important implications for understanding the host-response to Mtb, and possibly for improved vaccine design. Thus, this research proposal is focused on defining the mechanisms by which human CD8+ T cells recognize Mtb infected cells.
AIM 1 : Determine the relationship of HLA-E restricted T cell responses with TB disease status.
AIM 2 : Establish whether or not the Mtb-phagosome is a competent antigen processing organelle AIM 3: Characterize Mtb-reactive alpha beta TCR expressing thymocytes

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-IDM-A (02))
Program Officer
Parker, Tina M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Oregon Health and Science University
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Meermeier, Erin W; Harriff, Melanie J; Karamooz, Elham et al. (2018) MAIT cells and microbial immunity. Immunol Cell Biol 96:607-617
Greene, J M; Dash, P; Roy, S et al. (2017) MR1-restricted mucosal-associated invariant T (MAIT) cells respond to mycobacterial vaccination and infection in nonhuman primates. Mucosal Immunol 10:802-813
Harriff, Melanie J; Wolfe, Lisa M; Swarbrick, Gwendolyn et al. (2017) HLA-E Presents Glycopeptides from the Mycobacterium tuberculosis Protein MPT32 to Human CD8+ T cells. Sci Rep 7:4622
Meermeier, Erin W; Laugel, Bruno F; Sewell, Andrew K et al. (2016) Human TRAV1-2-negative MR1-restricted T cells detect S. pyogenes and alternatives to MAIT riboflavin-based antigens. Nat Commun 7:12506
Harriff, Melanie J; Karamooz, Elham; Burr, Ansen et al. (2016) Endosomal MR1 Trafficking Plays a Key Role in Presentation of Mycobacterium tuberculosis Ligands to MAIT Cells. PLoS Pathog 12:e1005524
Nyendak, Melissa; Swarbrick, Gwendolyn M; Duncan, Amanda et al. (2016) Adenovirally-Induced Polyfunctional T Cells Do Not Necessarily Recognize the Infected Target: Lessons from a Phase I Trial of the AERAS-402 Vaccine. Sci Rep 6:36355
Laugel, Bruno; Lloyd, Angharad; Meermeier, Erin W et al. (2016) Engineering of Isogenic Cells Deficient for MR1 with a CRISPR/Cas9 Lentiviral System: Tools To Study Microbial Antigen Processing and Presentation to Human MR1-Restricted T Cells. J Immunol 197:971-82
Gold, Marielle C; Napier, Ruth J; Lewinsohn, David M (2015) MR1-restricted mucosal associated invariant T (MAIT) cells in the immune response to Mycobacterium tuberculosis. Immunol Rev 264:154-66
Napier, Ruth J; Adams, Erin J; Gold, Marielle C et al. (2015) The Role of Mucosal Associated Invariant T Cells in Antimicrobial Immunity. Front Immunol 6:344
Harriff, Melanie J; Cansler, Meghan E; Toren, Katelynne Gardner et al. (2014) Human lung epithelial cells contain Mycobacterium tuberculosis in a late endosomal vacuole and are efficiently recognized by CD8? T cells. PLoS One 9:e97515

Showing the most recent 10 out of 29 publications