title: Between adaptive and innate immunity: TLR4-mediated perforin production by CD28null T-helper cells in ankylosing spondylitis.
abstract: CD3+CD4+CD28null and CD3+CD8+CD28null T cells are enriched in patients with immune-mediated diseases compared with healthy controls. This study shows that CD4+CD28null T cells express Toll-like receptors recognizing bacterial lipopolysaccharides in ankylosing spondylitis, psoriatic arthritis and rheumatoid arthritis. In ankylosing spondylitis, TLR4 (23.1 +/- 21.9%) and, to a smaller extent, TLR2 (4.1 +/- 5.8%) were expressed on CD4+CD28null T cells, whereas expression was negligible on CD4+CD28+ and CD8+ T cells. CD4+CD28null T cells produced perforin upon stimulation with lipopolysaccharide, and this effect was enhanced by autologous serum or recombinant soluble CD14. Perforin production could be prevented with blocking antibodies directed against CD14 or TLR4. Incubation of peripheral blood mononuclear cells with tumour necrosis factor alpha led to an upregulation of TLR4 and TLR2 on CD4+CD28null T cells in vitro, and treatment of patients with antibodies specifically directed against tumour necrosis factor alpha resulted in decreased expression of TLR4 and TLR2 on CD4+CD28null T cells in vivo. We describe here a new pathway for direct activation of cytotoxic CD4+ T cells by components of infectious pathogens. This finding supports the hypothesis that CD4+CD28null T cells represent an immunological link between the innate immune system and the adaptive immune system.
authors.affiliation: Department of Internal Medicine, Innsbruck Medical University, Austria. bernd.raffeiner@uibk.ac.at
authors.forename: Bernd
authors.initials: B
authors.lastname: Raffeiner
authors.forename: Christian
authors.initials: C
authors.lastname: Dejaco
authors.forename: Christina
authors.initials: C
authors.lastname: Duftner
authors.forename: Werner
authors.initials: W
authors.lastname: Kullich
authors.forename: Christian
authors.initials: C
authors.lastname: Goldberger
authors.forename: Sandra C
authors.initials: SC
authors.lastname: Vega
authors.forename: Michael
authors.initials: M
authors.lastname: Keller
authors.forename: Beatrix
authors.initials: B
authors.lastname: Grubeck-Loebenstein
authors.forename: Michael
authors.initials: M
authors.lastname: Schirmer
mesh_terms: D000328:Adult; D019138:Antibodies, Blocking / Q000494:pharmacology; D015535:Arthritis, Psoriatic / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018106:CD28 Antigens / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D005260:Female; D006801:Humans; D007109:Immunity / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D012333:RNA, Messenger / Q000378:metabolism; D013167:Spondylitis, Ankylosing / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D019138:Antibodies, Blocking; D018106:CD28 Antigens; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D012333:RNA, Messenger; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D054353:Perforin