Human CD8+ T-cells Recognizing Peptides From Mycobacterium Tuberculosis (Mtb) Presented by HLA-E Have an Unorthodox Th2-like, Multifunctional, Mtb Inhibitory Phenotype and Represent a Novel Human T-cell Subset

PLoS Pathog. 2015 Mar 24;11(3):e1004671. doi: 10.1371/journal.ppat.1004671. eCollection 2015 Mar.

Abstract

Mycobacterial antigens are not exclusively presented to T-cells by classical HLA-class Ia and HLA-class II molecules, but also through alternative antigen presentation molecules such as CD1a/b/c, MR1 and HLA-E. We recently described mycobacterial peptides that are presented in HLA-E and recognized by CD8+ T-cells. Using T-cell cloning, phenotyping, microbiological, functional and RNA-expression analyses, we report here that these T-cells can exert cytolytic or suppressive functions, inhibit mycobacterial growth, yet express GATA3, produce Th2 cytokines (IL-4,-5,-10,-13) and activate B-cells via IL-4. In TB patients, Mtb specific cells were detectable by peptide-HLA-E tetramers, and IL-4 and IL-13 were produced following peptide stimulation. These results identify a novel human T-cell subset with an unorthodox, multifunctional Th2 like phenotype and cytolytic or regulatory capacities, which is involved in the human immune response to mycobacteria and demonstrable in active TB patients' blood. The results challenge the current dogma that only Th1 cells are able to inhibit Mtb growth and clearly show that Th2 like cells can strongly inhibit outgrowth of Mtb from human macrophages. These insights significantly expand our understanding of the immune response in infectious disease.

Publication types

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

MeSH terms

  • Antigen Presentation*
  • Bacterial Proteins / immunology*
  • CD8-Positive T-Lymphocytes / immunology*
  • Cytokines / immunology
  • Female
  • GATA3 Transcription Factor / immunology
  • Histocompatibility Antigens Class I / immunology*
  • Humans
  • Macrophages / immunology
  • Male
  • Mycobacterium tuberculosis / immunology*
  • Peptides / immunology*
  • Th2 Cells / immunology*

Substances

  • Bacterial Proteins
  • Cytokines
  • GATA3 Transcription Factor
  • GATA3 protein, human
  • HLA-E antigen
  • Histocompatibility Antigens Class I
  • Peptides

Grant support

We acknowledge European Commission FP7 NEWTBVAC contract no. HEALTH.F3.2009 241745, European Commission FP7 ADITEC contract no. HEALTH.2011.1.4-4 280873 (the text represents the authors’ views and does not necessarily represent a position of the Commission who will not be liable for the use made of such information), The Netherlands Organization for Scientific Research (VENI grant 916.86.115), the Gisela Thier Foundation of the Leiden University Medical Center and the Netherlands Leprosy Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.