title: Effects of conventional immunosuppressive treatment on CD244+ (CD28null) and FOXP3+ T cells in the inflamed muscle of patients with polymyositis and dermatomyositis.
abstract: BACKGROUND
  T-cell infiltrates may persist in muscle tissue of polymyositis (PM) and dermatomyositis (DM) patients despite aggressive immunosuppressive treatment. Here, we investigated to what extent persistent T cells in affected muscle were FOXP3+, a marker for regulatory T cells (Tregs), or CD244+, a marker for CD28null T cells, and whether their presence correlated to clinical outcome. The sensitivity of CD28null T cells towards glucocorticoid and Treg-mediated immunosuppression was also investigated.
  
  
  METHODS
  Muscle biopsies from 16 newly diagnosed or untreated patients with PM/DM were investigated by immunohistochemistry for expression of CD3, FOXP3 and CD244 before and after treatment with glucocorticoids and immunosuppressive agents. For clinical evaluation, serum levels of creatine kinase, muscle performance (FI and MMT8), disease activity (MITAX) and disability (HAQ) were measured. In vitro suppressive effects of glucocorticoids and Tregs on T-cell activation were measured by CD69 upregulation.
  
  
  RESULTS
  Before treatment, CD244+ cells were present at higher proportions compared to FOXP3+ cells in the inflamed muscle. Following treatment, FOXP3+ cell numbers decreased while CD244+ cells persisted. Patients with impaired muscle function (<75 % FI) post-treatment had higher levels of CD244+ cells in the follow-up biopsy compared to those with FI >75 %. MITAX and HAQ correlated with the number of CD244+ cells post-treatment. CD4+CD28null T cells displayed lower sensitivity towards both glucocorticoid and Treg-mediated immunosuppression in vitro compared to their CD28+ counterparts.
  
  
  CONCLUSIONS
  Poor outcome in patients with myositis following immunosuppressive therapy was linked to persistence of CD244+ (CD28null) T cells in muscle tissue, suggesting their resistance against immunosuppression. A relative loss of regulatory T cells could also contribute to poor clinical outcome given their recently ascribed role in muscle tissue regeneration.
authors.affiliation: Rheumatology Unit, Department of Medicine, Center for Molecular Medicine, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jayesh M
authors.initials: JM
authors.lastname: Pandya
authors.affiliation: Rheumatology Unit, Department of Medicine, Center for Molecular Medicine, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ingela
authors.initials: I
authors.lastname: Loell
authors.affiliation: Rheumatology Unit, Department of Medicine, Center for Molecular Medicine, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Mohammad Shahadat
authors.initials: MS
authors.lastname: Hossain
authors.affiliation: Rheumatology Unit, Department of Medicine, Center for Molecular Medicine, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Mei
authors.initials: M
authors.lastname: Zong
authors.affiliation: Department of NVS, Division of Physiotherapy, Solna, Karolinska Institutet, Huddinge and Physiotherapy Clinic, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Helene
authors.initials: H
authors.lastname: Alexanderson
authors.affiliation: Rheumatology Unit, Department of Medicine, Center for Molecular Medicine, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden.|Present address: Department of Microbiology and Immunology, Institute for Biomedicine, Gothenburg University, Gothenburg, Sweden.
authors.forename: Sukanya
authors.initials: S
authors.lastname: Raghavan
authors.affiliation: Rheumatology Unit, Department of Medicine, Center for Molecular Medicine, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Lundberg
authors.affiliation: Rheumatology Unit, Department of Medicine, Center for Molecular Medicine, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden. vivianne.malmstrom@ki.se.
authors.forename: Vivianne
authors.initials: V
authors.lastname: Malmström
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000276:immunology; D003882:Dermatomyositis / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D005260:Female; D051858:Forkhead Transcription Factors / Q000276:immunology; D006801:Humans; D007150:Immunohistochemistry; D016130:Immunophenotyping; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000276:immunology / Q000473:pathology; D017285:Polymyositis / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D011446:Prospective Studies; D011971:Receptors, Immunologic / Q000276:immunology; D000071176:Signaling Lymphocytic Activation Molecule Family; D016176:T-Lymphocyte Subsets / Q000276:immunology*
chemical_list: D015703:Antigens, CD; C084093:CD244 protein, human; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007166:Immunosuppressive Agents; D011971:Receptors, Immunologic; D000071176:Signaling Lymphocytic Activation Molecule Family
keywords: Glucocorticoids; Inflammation; Myositis; T-lymphocyte; Treg cells