A broad profile of co-dominant epitopes shapes the peripheral Mycobacterium tuberculosis specific CD8+ T-cell immune response in South African patients with active tuberculosis

PLoS One. 2013;8(3):e58309. doi: 10.1371/journal.pone.0058309. Epub 2013 Mar 26.

Abstract

We studied major histocompatibility complex (MHC) class I peptide-presentation and nature of the antigen-specific CD8+ T-cell response from South African tuberculosis (TB) patients with active TB. 361 MHC class I binding epitopes were identified from three immunogenic TB proteins (ESAT-6 [Rv3875], Ag85B [Rv1886c], and TB10.4 [Rv0288], including amino acid variations for Rv0288, i.e., A10T, G13D, S27N, and A71S for MHC allotypes common in a South African population (e.g., human leukocyte antigen [HLA]-A*30, B*58, and C*07). Inter-allelic differences were identified regarding the broadness of the peptide-binding capacity. Mapping of frequencies of Mycobacterium tuberculosis (M. tb) antigen-specific CD8+ T-cells using 48 different multimers, including the newly constructed recombinant MHC class I alleles HLA-B*58:01 and C*0701, revealed a low frequency of CD8+ T-cell responses directed against a broad panel of co-dominant M. tb epitopes in the peripheral circulation of most patients. The antigen-specific responses were dominated by CD8+ T-cells with a precursor-like phenotype (CD45RA+CCR7+). The data show that the CD8+ T-cell response from patients with pulmonary TB (prior to treatment) is directed against subdominant epitopes derived from secreted and non-secreted M. tb antigens and that variant, natural occurring M. tb Rv0288 ligands, have a profound impact on T-cell recognition.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antigens, Bacterial / immunology*
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / pathology
  • Epitopes, T-Lymphocyte / immunology*
  • Female
  • HLA-B Antigens / immunology*
  • HLA-C Antigens / immunology*
  • Humans
  • Male
  • Mycobacterium tuberculosis / immunology*
  • South Africa
  • Tuberculosis, Pulmonary / epidemiology
  • Tuberculosis, Pulmonary / immunology*
  • Tuberculosis, Pulmonary / pathology

Substances

  • Antigens, Bacterial
  • Epitopes, T-Lymphocyte
  • HLA-B Antigens
  • HLA-B*58:01 antigen
  • HLA-C Antigens

Grant support

The study was funded in part by the EDCTP TB-NEAT study (MM, AZ) and grants from the Söderberg foundation, from VR, SIDA, HLF (Heart and Lung Foundation, Sweden) and Vinnova to MM. RA received a grant from Karolinska Institutet (KID), AGL received an Innovation Postdoctoral fellowship from the DST/NRF. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.