title: KLRG1 and PD-1 expression are increased on T-cells following tuberculosis-treatment and identify cells with different proliferative capacities in BCG-vaccinated adults.
abstract: In cancer and chronic infectious diseases, immune checkpoint-blockade of inhibitory receptors can enhance T-cell immunity. In tuberculosis (TB), a chronic infectious disease, prolonged antigen exposure can potentially drive terminal T-cell differentiation towards functional 'exhaustion': in human TB T-cells express PD-1 (programmed cell death protein-1) and CTLA-4 (cytotoxic T-lymphocyte-associated protein-4). However, in murine TB not PD-1 but rather killer cell lectin-like receptor subfamily-G1 (KLRG1) was a superior indicator of terminal T-cell differentiation. We therefore compared expression of KLRG1, PD-1 and CTLA-4 on T-cells in different stages of human TB, and also analysed their induction following BCG-vaccination. KLRG1, PD-1 and CTLA-4-expression were highest on in vitro BCG-stimulated CD4(+) T-cells following recent TB-treatment; KLRG1 and PD-1-expression on CD4(+) T-cells in active--but not latent--TB were only slightly increased compared to healthy donors. BCG-vaccination induced KLRG1-expression on BCG-stimulated CD8(+) but not CD4(+) T-cells, while neither PD-1 nor CTLA-4-expression increased. KLRG1-expressing CD8(+) T-cells exhibited markedly decreased proliferation, whereas PD-1(+) T-cells proliferated after in vitro BCG-stimulation. Thus, we demonstrate the presence of increased KLRG1-expressing T-cells in TB-treated individuals, and present KLRG1 as a marker of decreased human T-cell proliferation following BCG-vaccination. These results expand our understanding of cell-mediated immune control of mycobacterial infections.
authors.affiliation: Department of Infectious Diseases, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.
authors.forename: Mardi C
authors.initials: MC
authors.lastname: Boer
authors.affiliation: Department of Infectious Diseases, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.
authors.forename: Krista E
authors.initials: KE
authors.lastname: van Meijgaarden
authors.affiliation: Istituto Nazionale per le Malattie Infettive "L. Spallanzani", Via Portuense 292, Rome 00149, Italy.
authors.forename: Delia
authors.initials: D
authors.lastname: Goletti
authors.affiliation: Istituto Nazionale per le Malattie Infettive "L. Spallanzani", Via Portuense 292, Rome 00149, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Vanini
authors.affiliation: Department of Infectious Diseases, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.
authors.forename: Corine
authors.initials: C
authors.lastname: Prins
authors.affiliation: Department of Infectious Diseases, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. Electronic address: T.H.M.Ottenhoff@lumc.nl.
authors.forename: Tom H M
authors.initials: TH
authors.lastname: Ottenhoff
authors.affiliation: Department of Infectious Diseases, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.
authors.forename: Simone A
authors.initials: SA
authors.lastname: Joosten
mesh_terms: D000328:Adult; D000995:Antitubercular Agents / Q000627:therapeutic use*; D001500:BCG Vaccine / Q000627:therapeutic use*; D060908:CTLA-4 Antigen / Q000276:immunology / Q000378:metabolism; D016022:Case-Control Studies; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D055985:Latent Tuberculosis / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D037181:Lectins, C-Type / Q000276:immunology / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000276:immunology / Q000472:pathogenicity; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology / Q000378:metabolism*; D011971:Receptors, Immunologic; D012074:Remission Induction; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D013997:Time Factors; D015534:Trans-Activators / Q000276:immunology / Q000378:metabolism*; D016896:Treatment Outcome; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D015854:Up-Regulation; D014611:Vaccination; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents; D001500:BCG Vaccine; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C113413:KLRG1 protein, human; D037181:Lectins, C-Type; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D011971:Receptors, Immunologic; D015534:Trans-Activators
keywords: BCG-vaccination; CTLA-4; Human T-cells; Immune checkpoint-blockade; Immunity; Inhibitory receptors; KLRG1; PD-1; T-cell exhaustion; T-cells; Terminal differentiation; Tuberculosis