title: CD4+ and CD8+ CD28(null) T Cells Are Cytotoxic to Autologous Muscle Cells in Patients With Polymyositis.
abstract: Inflammatory T cell infiltrates in the skeletal muscle tissue of patients with polymyositis are dominated by CD28-negative effector (CD28(null) ) T cells of both the CD4 and CD8 lineage. These cells are potentially cytotoxic, and the aim of the present study was to develop a fully autologous cell culture system in which to investigate the functional contribution of such CD28(null) T cells to myotoxicity.
  
  
  
  In vitro cocultures of autologous skeletal muscle cells and T cell subsets obtained from 5 polymyositis patients were performed. Myotoxicity of T cells was quantified by calcein release and flow cytometric analyses. T cell degranulation was blocked with concanamycin A. Specific blocking of perforin, cytokines, and HLA was performed using antibodies.
  
  
  
  Both CD4+CD28(null) and CD8+CD28(null) T cells induced more muscle cell death than did their CD28+ counterparts. Differentiated muscle cells (myotubes) were more sensitive to T cell-mediated cell death than were their precursors (myoblasts). Both CD8+ and CD4+ CD28(null) T cells displayed perforin polarization toward muscle cells and secreted higher levels of granzyme B and interferon-γ (IFNγ) in coculture than did CD28+ T cells. The myotoxic effects of CD28(null) T cells were reduced upon the blocking of perforin, cytokines, and HLA. Addition of IFNγ or tumor necrosis factor did not induce skeletal muscle cell death in the absence of T cells; however, it did up-regulate HLA expression on muscle cells.
  
  
  
  Myotoxicity of CD4+ and CD8+ CD28(null) T cells is mediated by directed perforin-dependent killing and can be further influenced by IFNγ-induced HLA expression on muscle cells. The data suggest that CD28(null) T cells are key effector cells that contribute to the muscle cell damage in polymyositis.
authors.affiliation: Karolinska University Hospital Solna, Sweden, and Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jayesh M
authors.initials: JM
authors.lastname: Pandya
authors.affiliation: Karolinska University Hospital Solna, Sweden, and Karolinska Institutet, Stockholm, Sweden.
authors.forename: Paulius
authors.initials: P
authors.lastname: Venalis
authors.affiliation: KTH Royal Institute of Technology, Stockholm, Sweden.
authors.forename: Lubna
authors.initials: L
authors.lastname: Al-Khalili
authors.affiliation: Karolinska University Hospital Solna, Sweden, and Karolinska Institutet, Stockholm, Sweden.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Shahadat Hossain
authors.affiliation: Karolinska University Hospital Solna, Sweden, and Karolinska Institutet, Stockholm, Sweden.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Stache
authors.affiliation: Karolinska University Hospital Solna, Sweden, and Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Lundberg
authors.affiliation: Karolinska University Hospital Solna, Sweden, and Karolinska Institutet, Stockholm, Sweden.
authors.forename: Vivianne
authors.initials: V
authors.lastname: Malmström
authors.affiliation: Andreas E. R. Fasth, PhD: Karolinska lnstitutet, Schering-Plough, MSD, and Novartis, Stockholm, Sweden.
authors.forename: Andreas E R
authors.initials: AE
authors.lastname: Fasth
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018106:CD28 Antigens; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology*; D018929:Cell Culture Techniques; D018920:Coculture Techniques; D006801:Humans; D008875:Middle Aged; D032342:Muscle Cells; D017285:Polymyositis / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D018106:CD28 Antigens