title: Smoking activates cytotoxic CD8+T cells and causes survivin release in rheumatoid arthritis.
abstract: CD8+T cells have an emerging role in RA. Resent research indicates a causal relationship between the non-exhausted state of CD8+T cells, defined by lost function of PD-1, and development of arthritis. We investigated how smoking contributes to the non-exhausted phenotype of CD8+T cells and cause survivin release to serum. We compared serum survivin levels between smokers and non-smokers in 252 RA and 168 healthy subjects. Nicotine effects on CD8+T cells were studied in peripheral blood of smoking women, bone marrow of nicotine treated mice and in sorted CD8 spleen cells in vitro using flow cytometry and quantitative PCR. Smoking increased the frequency of survivin release in serum of healthy women (OR 3.64, p = 0.025) and in RA patients (OR 1.98, p = 0.039). CD8+T cells of smokers gained a non-exhausted PD-1 deficient phenotype. Expression of the cytotoxic marker CD107 correlated to survivin levels in serum. In the experimental setting, nicotine exposure led to an accumulation of non-exhausted PD-1-IL-7R+CD8+T cells in the bone marrow that is abundant with survivin producing cells. The production of the cytolytic protein perforin in bone marrow correlated to serum survivin levels. In vitro stimulation of nicotinic receptors on murine CD8+T cells induced repressive transcription factors T-bet and Blimp-1 in support of the non-exhausted phenotype. We conclude that nicotine contributes to autoimmunity by supporting the non-exhausted state of CD8+T cells resulting in the release of survivin. This presents a new mechanism by which smoking may contribute to the pathogenesis of RA.
authors.affiliation: Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, The University of Gothenburg, Göteborg, Sweden. Electronic address: caroline.wasen@rheuma.gu.se.
authors.forename: Caroline
authors.initials: C
authors.lastname: Wasén
authors.affiliation: Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, The University of Gothenburg, Göteborg, Sweden. Electronic address: minnaturkkila@outlook.com.
authors.forename: Minna
authors.initials: M
authors.lastname: Turkkila
authors.affiliation: The Krefting Research Centre, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, The University of Gothenburg, Göteborg, Sweden. Electronic address: apostolos.bossios@lungall.gu.se.
authors.forename: Apostolos
authors.initials: A
authors.lastname: Bossios
authors.affiliation: Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, The University of Gothenburg, Göteborg, Sweden. Electronic address: malin.erlandsson@gu.se.
authors.forename: Malin
authors.initials: M
authors.lastname: Erlandsson
authors.affiliation: Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, The University of Gothenburg, Göteborg, Sweden. Electronic address: karin.andersson@rheuma.gu.se.
authors.forename: Karin M
authors.initials: KM
authors.lastname: Andersson
authors.affiliation: The Krefting Research Centre, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, The University of Gothenburg, Göteborg, Sweden. Electronic address: linda.ekerljung@lungall.gu.se.
authors.forename: Linda
authors.initials: L
authors.lastname: Ekerljung
authors.affiliation: The Krefting Research Centre, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, The University of Gothenburg, Göteborg, Sweden. Electronic address: carina.malmhall@lungall.gu.se.
authors.forename: Carina
authors.initials: C
authors.lastname: Malmhäll
authors.affiliation: Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, The University of Gothenburg, Göteborg, Sweden. Electronic address: mikael.brisslert@gu.se.
authors.forename: Mikael
authors.initials: M
authors.lastname: Brisslert
authors.affiliation: Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, The University of Gothenburg, Göteborg, Sweden. Electronic address: sofia.silfversward@rheuma.gu.se.
authors.forename: Sofia
authors.initials: S
authors.lastname: Töyrä Silfverswärd
authors.affiliation: The Krefting Research Centre, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, The University of Gothenburg, Göteborg, Sweden. Electronic address: bo.lundback@gu.se.
authors.forename: Bo
authors.initials: B
authors.lastname: Lundbäck
authors.affiliation: Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, The University of Gothenburg, Göteborg, Sweden. Electronic address: maria.bokarewa@rheuma.gu.se.
authors.forename: Maria I
authors.initials: MI
authors.lastname: Bokarewa
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D015415:Biomarkers; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D051034:Inhibitor of Apoptosis Proteins / Q000096:biosynthesis* / Q000097:blood; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009538:Nicotine / Q000494:pharmacology; D010641:Phenotype; D061026:Programmed Cell Death 1 Receptor / Q000172:deficiency / Q000378:metabolism; D012907:Smoking; D000077022:Survivin; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D055815:Young Adult
chemical_list: C107489:BIRC5 protein, human; D015415:Biomarkers; D051034:Inhibitor of Apoptosis Proteins; D061026:Programmed Cell Death 1 Receptor; D000077022:Survivin; D009538:Nicotine
keywords: CD8(+) T cells; Interleukin-7 receptor; Programmed cell death 1; Rheumatoid arthritis; Smoking; Survivin