title: 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.
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.
authors: Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.
authors: Krista E
authors: KE
authors: van Meijgaarden
authors: Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.
authors: Mariëlle C
authors: MC
authors: Haks
authors: Central Laboratory for Advanced Diagnostic and Biomedical Research (CLADIBIOR), Dipartimento di Biopatologia e Biotecnologie Mediche e Forensi, Università di Palermo, Palermo, Italy.
authors: Nadia
authors: N
authors: Caccamo
authors: Central Laboratory for Advanced Diagnostic and Biomedical Research (CLADIBIOR), Dipartimento di Biopatologia e Biotecnologie Mediche e Forensi, Università di Palermo, Palermo, Italy.
authors: Francesco
authors: F
authors: Dieli
authors: Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.
authors: Tom H M
authors: TH
authors: Ottenhoff
authors: Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.
authors: Simone A
authors: SA
authors: Joosten
mesh_terms: D017951:Antigen Presentation; D001426:Bacterial Proteins / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D016207:Cytokines / Q000276:immunology; D005260:Female; D050990:GATA3 Transcription Factor / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D008264:Macrophages / Q000276:immunology; D008297:Male; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D010455:Peptides / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*; D000097625:HLA-E Antigens
chemical_list: D001426:Bacterial Proteins; D016207:Cytokines; D050990:GATA3 Transcription Factor; D015395:Histocompatibility Antigens Class I; D010455:Peptides; D000097625:HLA-E Antigens; C494749:GATA3 protein, human