Central role of thrombospondin-1 in the activation and clonal expansion of inflammatory T cells.
Thrombospondin-1 (TSP) is a transiently expressed matricellular protein known to promote chemotaxis of leukocytes to inflammatory sites. However, TSP and its receptor CD36 are abundantly expressed in chronically inflamed tissues such as the rheumatoid synovium. Here, we show that TSP provides the costimulatory signal that is necessary for the activation of autoreactive T cells. Data presented reveal that TSP-mediated costimulation is achieved through its independent interaction with CD36 on APCs and with CD47 on T cells. We propose that a CD47-TSP-CD36 trimolecular complex is a novel costimulatory pathway that significantly decreases the threshold of T cell activation. Consistent with the paradigm that lesions in rheumatoid synovitis are sites of antigenic recognition, the characteristic focal expression of TSP on APCs such as macrophages and fibroblast-like synoviocytes suggest a central role of TSP in the expansion of tissue-infiltrating T cells.
Vallejo
A N
AN
Division of Rheumatology, Department of Internal Medicine, Mayo Clinic-Foundation, Rochester, MN 55905, USA. vallejo.abbe@mayo.edu
Mügge
L O
LO
Klimiuk
P A
PA
Weyand
C M
CM
Goronzy
J J
JJ
D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D001172:Arthritis, Rheumatoid / Q000276:immunology; D001704:Biopolymers / Q000378:metabolism; D018955:CD36 Antigens / Q000378:metabolism; D051928:CD47 Antigen; D002352:Carrier Proteins / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D002460:Cell Line; D002999:Clone Cells; D018920:Coculture Techniques; D005347:Fibroblasts / Q000276:immunology / Q000473:pathology; D006684:HLA-DR Antigens / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D013583:Synovial Membrane / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology*; D019700:Thrombospondin 1 / Q000378:metabolism / Q000502:physiology*
D015703:Antigens, CD; D001704:Biopolymers; D018955:CD36 Antigens; D051928:CD47 Antigen; C497894:CD47 protein, human; D002352:Carrier Proteins; D006684:HLA-DR Antigens; D019700:Thrombospondin 1