Mycobacterium tuberculosis peptides presented by HLA-E molecules are targets for human CD8 T-cells with cytotoxic as well as regulatory activity

Simone A. Joosten, Krista E. van Meijgaarden, Pascale C. van Weeren, Fatima Kazi, Annemieke Geluk, Nigel D.L. Savage, Jan W. Drijfhout, Darren R Flower, Willem A. Hanekom, Michèl R. Klein, Tom H.M. Ottenhoff

Research output: Contribution to journalArticle

Abstract

Tuberculosis (TB) is an escalating global health problem and improved vaccines against TB are urgently needed. HLA-E restricted responses may be of interest for vaccine development since HLA-E displays very limited polymorphism (only 2 coding variants exist), and is not down-regulated by HIV-infection. The peptides from Mycobacterium tuberculosis (Mtb) potentially presented by HLA-E molecules, however, are unknown. Here we describe human T-cell responses to Mtb-derived peptides containing predicted HLA-E binding motifs and binding-affinity for HLA-E. We observed CD8(+) T-cell proliferation to the majority of the 69 peptides tested in Mtb responsive adults as well as in BCG-vaccinated infants. CD8(+) T-cells were cytotoxic against target-cells transfected with HLA-E only in the presence of specific peptide. These T cells were also able to lyse M. bovis BCG infected, but not control monocytes, suggesting recognition of antigens during mycobacterial infection. In addition, peptide induced CD8(+) T-cells also displayed regulatory activity, since they inhibited T-cell proliferation. This regulatory activity was cell contact-dependent, and at least partly dependent on membrane-bound TGF-beta. Our results significantly increase our understanding of the human immune response to Mtb by identification of CD8(+) T-cell responses to novel HLA-E binding peptides of Mtb, which have cytotoxic as well as immunoregulatory activity.
Original languageEnglish
Article numbere1000782
Pages (from-to)e1000782
JournalPlos Pathogens
Volume6
Issue number2
DOIs
Publication statusPublished - Feb 2010

Bibliographical note

© 2010 Joosten et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Keywords

  • adult
  • antigen presentation
  • bacterial antigens
  • CD8-positive T-lymphocytes
  • cell separation
  • T-lymphocyte epitopes,
  • flow cytometry
  • HLA antigens
  • histocompatibility antigens class I
  • humans
  • infant
  • Lymphocyte activation
  • mycobacterium tuberculosis
  • T-lymphocyte subsets
  • cytotoxic T-lymphocytes
  • regulatory T-lymphocytes
  • tuberculosis
  • tuberculosis vaccines

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    Joosten, S. A., van Meijgaarden, K. E., van Weeren, P. C., Kazi, F., Geluk, A., Savage, N. D. L., Drijfhout, J. W., Flower, D. R., Hanekom, W. A., Klein, M. R., & Ottenhoff, T. H. M. (2010). Mycobacterium tuberculosis peptides presented by HLA-E molecules are targets for human CD8 T-cells with cytotoxic as well as regulatory activity. Plos Pathogens, 6(2), e1000782. [e1000782]. https://doi.org/10.1371/journal.ppat.1000782