title: Skin-Resident Effector Memory CD8+CD28-T Cells Exhibit a Profibrotic Phenotype in Patients with Systemic Sclerosis.
abstract: Loss of CD28 expression by CD8+T cells occurs with age and during chronic inflammatory conditions. CD8+CD28-T cells are a heterogeneous cell subpopulation whose function ranges from immunosuppressive to effector. Here we analyzed the role of CD8+CD28-T cells in the pathogenesis of systemic sclerosis (SSc), a connective tissue disorder characterized by autoimmunity, vasculopathy, and extensive cutaneous and visceral fibrosis. We show that the frequency of CD8+CD28-T cells is increased in the blood and affected skin of SSc patients, independent of patient age, and correlates with the extent of skin fibrosis. We found that most skin-tropic CD8+CD28-T cells are resident in the skin lesions of patients in the early stage of the disease, exhibit an effector memory phenotype, and present a strong cytolytic activity ex vivo. Skin-resident and circulating SSc CD8+CD28-T cells produce high levels of the profibrotic cytokine IL-13, which induces collagen production by normal and SSc dermal fibroblasts. Thus, our findings indicate that CD8+CD28-T cells represent a pathogenic T-cell subset in SSc and likely play a critical role in the early stage of SSc skin disease.
authors.affiliation: Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA; Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Adriana T
authors.initials: AT
authors.lastname: Larregina
authors.affiliation: Department of Medicine, Division of Rheumatology and Clinical Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Robyn T
authors.initials: RT
authors.lastname: Domsic
authors.affiliation: Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Donna B
authors.initials: DB
authors.lastname: Stolz
authors.affiliation: Department of Medicine, Division of Rheumatology and Clinical Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Medsger
authors.affiliation: Department of Medicine, Division of Rheumatology and Clinical Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Lafyatis
authors.affiliation: Department of Medicine, Division of Rheumatology and Clinical Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA. Electronic address: paf23@pitt.edu.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Fuschiotti
mesh_terms: D000328:Adult; D000368:Aged; D018106:CD28 Antigens / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D016022:Case-Control Studies; D003094:Collagen / Q000378:metabolism; D005260:Female; D005355:Fibrosis; D006801:Humans; D018793:Interleukin-13 / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D012595:Scleroderma, Systemic / Q000276:immunology / Q000503:physiopathology*; D012867:Skin / Q000276:immunology / Q000473:pathology*; D055815:Young Adult
chemical_list: D018106:CD28 Antigens; D018793:Interleukin-13; D003094:Collagen