Comprehensive definition of human immunodominant CD8 antigens in tuberculosis.

Despite widespread use of the Bacillus Calmette-Guerin vaccine, tuberculosis, caused by infection with Mycobacterium tuberculosis , remains a leading cause of morbidity and mortality worldwide. As CD8 ⁺ T cells are critical to tuberculosis host defense and a phase 2b vaccine trial of modified vaccinia Ankara expressing Ag85a that failed to demonstrate efficacy, also failed to induce a CD8 ⁺ T cell response, an effective tuberculosis vaccine may need to induce CD8 ⁺ T cells. However, little is known about CD8, as compared to CD4, antigens in tuberculosis. Herein, we report the results of the first ever HLA allele independent genome-wide CD8 antigen discovery program. Using CD8 ⁺ T cells derived from humans with latent tuberculosis infection or tuberculosis and an interferon-γ ELISPOT assay, we screened a synthetic peptide library representing 10% of the Mycobacterium tuberculosis proteome, selected to be enriched for Mycobacterium tuberculosis antigens. We defined a set of immunodominant CD8 antigens including part or all of 74 Mycobacterium tuberculosis proteins, only 16 of which are previously known CD8 antigens. Immunogenicity was associated with the degree of expression of mRNA and protein. Immunodominant antigens were enriched in cell wall proteins with preferential recognition of Esx protein family members, and within proteins comprising the Mycobacterium tuberculosis secretome. A validation study of immunodominant antigens demonstrated that these antigens were strongly recognized in Mycobacterium tuberculosis -infected individuals from a tuberculosis endemic region in Africa. The tuberculosis vaccine field will likely benefit from this greatly increased known repertoire of CD8 immunodominant antigens and definition of properties of Mycobacterium tuberculosis proteins important for CD8 antigenicity.
Competing Interests: COMPETING INTERESTS Aeras TB Vaccine Foundation, a non-profit organization, has licensed technology from OHSU of which Drs. David and Deborah Lewinsohn are inventors and which is used in this research. In addition, OHSU and Drs. David Lewinsohn, Deborah Lewinsohn, and Melissa Nyendak have a financial interest in, and Ms. Cansler, Ms. Null, and Ms. Swarbrick are employees of, ViTi, a company that may have a commercial interest in the results of this research and technology. These potential individual and institutional conflicts of interest have been reviewed and managed by OHSU.