Comprehensive definition of human immunodominant CD8 antigens in tuberculosis

Abstract

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.

Synergy between tuberculin skin test and proliferative T cell responses to PPD or cell-membrane antigens of Mycobacterium tuberculosis for detection of latent TB infection in a high disease-burden setting

“…We initially compared the proliferative responses of CD4+ and CD8+ cells to PPD and MTBMem antigens since both subsets of T (CD3+) cells contribute to overall T cell-mediated immunity against MTB [ 28 ]. Both showed comparable responses to PPD and PHA (a T cell mitogen), though the response to MTBMem differed significantly (P <0.05, Fig 2 and S3 Table ).…”

Mycobacterium tuberculosis-specific CD4+ and CD8+ T cells differ in their capacity to recognize infected macrophages

“…TB10.4 (EsxH) is an ESAT-6-like protein secreted by the ESX-3 type VII secretion system, important in iron and zinc acquisition, and although its requirement for bacterial growth depends on the culture conditions, it is essential for Mtb growth in macrophages and virulence in vivo [ 16 – 18 ]. Following Mtb infection, TB10.4 is a target of CD4 + and CD8 + T cell responses in humans and mice [ 19 – 23 ]. In Mtb-infected mice, TB10.4 elicits immunodominant responses in both BALB/c and C57BL/6 mice, and 30–50% of lung CD8 + T cells are specific to single epitopes [ 19 , 20 ].…”

Proof of concept in utilizing in-trans surface display system of Lactobacillus plantarum as mucosal tuberculosis vaccine via oral administration in mice

“…In this study, different types of M. tuberculosis antigens of Ag85B, CFP-10, ESAT-6, Rv2031 and Rv0475 were chosen since these antigens are considered immunodominant proteins with ability to induce protective immune responses in several different animal models [ 15 , 16 ] as well as in human beings [ 17 ]. The combinations of these immunodominant antigens as multiple antigen fusion protein, similar to the approach of the current tuberculosis subunit trial vaccines [ 18 ], can represent a broad epitopic repertoire that leads to improved activation of helper as well as cytotoxic T cell responses.…”