Mycobacterium tuberculosis Peptides Presented by HLA-E Molecules Are Targets for Human CD8+ T-Cells with Cytotoxic as well as Regulatory Activity

PLoS Pathogens

Jan W. Drijfhout¹  Krista E. van Meijgaarden²  Simone A. Joosten²  Michèl R. Klein²  Annemieke Geluk²  Pascale C. van Weeren²  Nigel D. L. Savage²  Tom H. M. Ottenhoff²  Fatima Kazi²  Willem A. Hanekom³  Darren R. Flower⁴ 

[1] Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands;Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands;South African Tuberculosis Vaccine Initiative, School of Child and Adolescent Health, University of Cape Town, Cape Town, South Africa;The Jenner Institute, University of Oxford, Oxford, United Kingdom

关键词: T cells;    Mycobacterium tuberculosis;    Cytotoxic T cells;    Binding analysis;    Tuberculosis;    Antigen-presenting cells;    Monocytes;    Immune response;   

DOI  :  10.1371/journal.ppat.1000782

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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-β. 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.

【 授权许可】

CC BY