Interactions of thrombospondins with alpha4beta1 integrin and CD47 differentially modulate T cell behavior.
Thrombospondin (TSP)-1 has been reported to modulate T cell behavior both positively and negatively. We found that these opposing responses arise from interactions of TSP1 with two different T cell receptors. The integrin alpha4beta1 recognizes an LDVP sequence in the NH2-terminal domain of TSP1 and was required for stimulation of T cell adhesion, chemotaxis, and matrix metalloproteinase gene expression by TSP1. Recognition of TSP1 by T cells depended on the activation state of alpha4beta1 integrin, and TSP1 inhibited interaction of activated alpha4beta1 integrin on T cells with its counter receptor vascular cell adhesion molecule-1. The alpha4beta1 integrin recognition site is conserved in TSP2. A recombinant piece of TSP2 containing this sequence replicated the alpha4beta1 integrin-dependent activities of TSP1. The beta1 integrin recognition sites in TSP1, however, were neither necessary nor sufficient for inhibition of T cell proliferation and T cell antigen receptor signaling by TSP1. A second TSP1 receptor, CD47, was not required for some stimulatory responses to TSP1 but played a significant role in its T cell antigen receptor antagonist and antiproliferative activities. Modulating the relative expression or function of these two TSP receptors could therefore alter the direction or magnitude of T cell responses to TSPs.
Li
Zhuqing
Z
Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1500, USA.
Calzada
Maria J
MJ
Sipes
John M
JM
Cashel
Jo Anne
JA
Krutzsch
Henry C
HC
Annis
Douglas S
DS
Mosher
Deane F
DF
Roberts
David D
DD
D015703:Antigens, CD / Q000378:metabolism / Q000502:physiology*; D001665:Binding Sites; D051928:CD47 Antigen; D002352:Carrier Proteins / Q000378:metabolism / Q000502:physiology*; D002455:Cell Division; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000502:physiology; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism; D006493:Heparin / Q000378:metabolism; D006801:Humans; D039041:Integrin alpha4beta1; D016023:Integrins / Q000378:metabolism / Q000502:physiology*; D019169:Jurkat Cells; D016201:Receptors, Lymphocyte Homing / Q000378:metabolism / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000502:physiology*; D019700:Thrombospondin 1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D019699:Thrombospondins / Q000235:genetics / Q000378:metabolism; D000099262:Thrombospondin 2
D015703:Antigens, CD; D051928:CD47 Antigen; D002352:Carrier Proteins; D019812:Heparan Sulfate Proteoglycans; D006493:Heparin; D039041:Integrin alpha4beta1; D016023:Integrins; D016201:Receptors, Lymphocyte Homing; D011994:Recombinant Proteins; D019700:Thrombospondin 1; D019699:Thrombospondins; D000099262:Thrombospondin 2; C497894:CD47 protein, human