title: Functional subsets of CD4 T cells in rheumatoid synovitis.
abstract: OBJECTIVE
  To identify the functional properties of CD4+ CD28- T cells, which accumulate and clonally expand in patients with rheumatoid arthritis (RA).
  
  
  METHODS
  The gene expression of molecules involved in T cell effector functions was compared in CD4+ CD28- and CD4+ CD28+ T cell clones. The expression of differentially up-regulated genes was confirmed by flow cytometry of T cells and by 2-color immunohistochemistry of rheumatoid synovial tissue. Cytotoxicity of CD4+ CD28- T cells was tested by anti-CD3 redirected lysis of Fc receptor-positive target cells.
  
  
  RESULTS
  CD4+ CD28- T cell clones lacked messenger RNA for the CD40 ligand (CD40L) but transcribed the perforin gene. Perforin was also found in freshly isolated CD4+ CD28- peripheral blood lymphocytes from RA patients. CD4+ CD28-, but not CD4+ CD28+, T cell clones lysed Fc receptor-bearing target cells. CD4+ perforin-positive T cells were present in the synovial tissue, where their frequency correlated with the expansion of the CD4+ CD28- compartment in the periphery. Among tissue-infiltrating CD4+ T cells, only the CD40L-negative subset expressed perforin transcripts.
  
  
  CONCLUSIONS
  Clonally expanded CD4+ CD28- T cells are functionally specialized for killing, while they lack the ability to provide B cell help. Tissue-infiltrating CD4+ T cells can be subdivided phenotypically and functionally into at least 2 distinct subsets based on their expression of perforin and CD40L. Because the expansion of CD4+ CD28- T cells is associated with extraarticular RA, T cell-mediated cytotoxicity may be particularly important in these most severe complications of RA.
authors.affiliation: Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: T
authors.initials: T
authors.lastname: Namekawa
authors.forename: U G
authors.initials: UG
authors.lastname: Wagner
authors.forename: J J
authors.initials: JJ
authors.lastname: Goronzy
authors.forename: C M
authors.initials: CM
authors.lastname: Weyand
mesh_terms: D001172:Arthritis, Rheumatoid / Q000097:blood / Q000276:immunology* / Q000473:pathology*; D018106:CD28 Antigens / Q000097:blood; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D019013:CD40 Antigens / Q000032:analysis; D023201:CD40 Ligand; D002999:Clone Cells / Q000378:metabolism; D053804:Granzymes; D006801:Humans; D008562:Membrane Glycoproteins / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D012697:Serine Endopeptidases / Q000096:biosynthesis / Q000235:genetics; D013585:Synovitis / Q000276:immunology* / Q000473:pathology*; D016176:T-Lymphocyte Subsets / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000502:physiology
chemical_list: D018106:CD28 Antigens; D019013:CD40 Antigens; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin; D023201:CD40 Ligand; C509213:GZMB protein, human; D053804:Granzymes; D012697:Serine Endopeptidases