Journal Article

Rv3615c is a highly immunodominant RD1 (Region of Difference 1)-dependent secreted antigen specific for Mycobacterium tuberculosis infection

Garces, Alejandra, Low, Jeffrey, Kon, Onn M, Lalvani, Ajit, Hingley-Wilson, Suzanne M, Wickremasinghe, Melissa, Millington, Kerry A, Fortune, Sarah M

2011

Overview

The 6-kDa early secretory antigenic target of Mycobacterium tuberculosis (ESAT-6) and the 10-kDa culture filtrate antigen (CFP-10), encoded in region of difference 1 (RD1) and secreted by the ESAT-6 system 1 (Esx-1) secretion system, are the most immunodominant and highly M. tuberculosis (MTB)-specific antigens. These attributes are responsible for their primary importance in tuberculosis (TB) immunodiagnosis and vaccine development. Rv3615c [Esx-1 substrate protein C (EspC)], encoded outside RD1, is similar in size and sequence homology to CFP-10 and ESAT-6, suggesting it might be a target of cellular immunity in TB. Using ex vivo enzyme-linked immunospot- and flow cytometry-based cytokine-secretion assay, we comprehensively assessed cellular immune responses to EspC in patients with active TB, latently infected persons, and uninfected bacillus Calmette-Guérin (BCG)-vaccinated controls. EspC was at least as immunodominant as ESAT-6 and CFP-10 in both active and latent TB infection. EspC contained broadly recognized CD4⁺ and CD8⁺ epitopes, inducing a predominantly CD4⁺ T-cell response that comprised functional T-cell subsets secreting both IFN-γ and IL-2 as well as functional T-cell subsets secreting only IFN-γ. Surprisingly, T-cell responses to EspC were as highly specific (93%) for MTB infection as responses to ESAT-6 and CFP-10, with only 2 of 27 BCG-vaccinated controls responding to each antigen. Using quantitative proteomics and metabolically labeled mutant and genetically complemented MTB strains, we identified the mechanism of the specificity of anti-EspC immunity as the Esx-1 dependence of EspC secretion. The high immunodominance of EspC, equivalent to that of ESAT-6 and CFP-10, makes it a TB vaccine candidate, and its high specificity confers strong potential for T-cell-based immunodiagnosis.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Antigens / Antigens, Bacterial - immunology / Bacteria / Bacterial Proteins - immunology / BCG / BCG Vaccine / Biological Sciences / CD4 antigen / CD4-positive T-lymphocytes / CD8 antigen / Cell culture / cell-mediated immunity / Cellular immunity / culture filtrates / Cytokines / Enzyme-Linked Immunospot Assay / Epitopes / ESAT-6 antigen / Filtrate / Flow Cytometry / gamma -Interferon / Homology / Humans / Immune response / Immunity / Immunity (cell-mediated) / Immunodiagnosis / Immunodominance / Immunodominant Epitopes - immunology / Infection / Infections / interferon-gamma / Interleukin 2 / Latent infection / Latent tuberculosis / Lymphocytes T / Medical diagnosis / mutants / Mycobacterium tuberculosis / Mycobacterium tuberculosis - immunology / patients / people / protein C / Proteins / Proteomics / Secretion / sequence homology / serodiagnosis / T cell receptors / T lymphocytes / T-Lymphocyte Subsets - immunology / Tuberculosis / Tuberculosis - diagnosis / Tuberculosis - immunology / Tuberculosis vaccine / Vaccination / vaccine development / Vaccines