Synoviocyte-mediated expansion of inflammatory T cells in rheumatoid synovitis is dependent on CD47-thrombospondin 1 interaction.
Fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis elicit spontaneous proliferation of autologous T cells in an HLA-DR and CD47 costimulation-dependent manner. T cell costimulation through CD47 is attributed to specific interaction with thrombospondin-1 (TSP1), a CD47 ligand displayed on FLS. CD47 binding by FLS has broad biological impact that includes adhesion and the triggering of specific costimulatory signals. TSP1(+) FLS are highly adhesive to T cells and support their aggregation and growth in situ. Long-term cultures of T cells and FLS form heterotypic foci that are amenable to propagation without exogenous growth factors. T cell adhesion and aggregate formation on TSP1(+) FLS substrates are inhibited by CD47-binding peptides. In contrast, FLS from arthroscopy controls lack adhesive or T cell growth-promoting activities. CD47 stimulation transduces a costimulatory signal different from that of CD28, producing a gene expression profile that included induction of ferritin L chain, a component of the inflammatory response. Ferritin L chain augments CD3-induced proliferation of T cells. Collectively, these results demonstrate the active role of FLS in the recruitment, activation, and expansion of T cells in a CD47-dependent manner. Because TSP1 is abundantly expressed in the rheumatoid synovium, CD47-TSP1 interaction is proposed to be a key component of an FLS/T cell regulatory circuit that perpetuates the inflammatory process in the rheumatoid joint.
Vallejo
Abbe N
AN
Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA.
Yang
Hongyu
H
Klimiuk
Piotr A
PA
Weyand
Cornelia M
CM
Goronzy
Jörg J
JJ
D000276:Adjuvants, Immunologic / Q000096:biosynthesis / Q000502:physiology; D015703:Antigens, CD / Q000378:metabolism / Q000502:physiology*; D001052:Apoferritins; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000473:pathology; D051928:CD47 Antigen; D002352:Carrier Proteins / Q000378:metabolism / Q000502:physiology*; D002448:Cell Adhesion / Q000235:genetics / Q000276:immunology; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D002999:Clone Cells; D018920:Coculture Techniques; D005293:Ferritins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D013583:Synovial Membrane / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D013585:Synovitis / Q000276:immunology* / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000378:metabolism / Q000473:pathology*; D019699:Thrombospondins / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*
D000276:Adjuvants, Immunologic; D015703:Antigens, CD; D051928:CD47 Antigen; C497894:CD47 protein, human; D002352:Carrier Proteins; D019699:Thrombospondins; D005293:Ferritins; D001052:Apoferritins