ZIA SC 009174 (ZIA) | |||
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Title | Roles of Glycoconjugates and Redox Signaling in Tumor Biology | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Roberts, David | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $338,669 | Project Dates | 00/00/0000 - 00/00/0000 |
Fiscal Year | 2013 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Autoimmune Diseases (20.0%) Cancer (100.0%) Digestive Diseases (10.0%) Inflammatory Bowel Disease (10.0%) |
Breast (10.0%) Colon/Rectum (10.0%) Non Hodgkins Lymphoma (10.0%) Ovarian Cancer (10.0%) Vascular Disease (10.0%) |
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Research Type | |||
Systemic Therapies - Discovery and Development | |||
Abstract | |||
Thrombospondin-1 is a potent suppressor of T cell activation via its receptor CD47. However, the precise mechanism for this inhibition remains unclear. Because H2S is an endogenous potentiator of T cell activation and is necessary for full T cell activation, we hypothesized that thrombospondin-1 signaling through CD47 inhibits T cell activation by antagonizing H2S signaling. Primary T cells from thrombospondin-1 null mice were more sensitive to H2S-dependent activation assessed by proliferation and induction of interleukin-2 and CD69 mRNAs. Exogenous thrombospondin-1 inhibited H2S responses in wild type and thrombospondin-1 null T cells but enhanced the same responses in CD47 null T cells. Fibronectin, which shares integrin and glycosaminoglycan binding properties with thrombospondin-1 but not CD47 binding, did not inhibit H2S signaling. A CD47-binding peptide derived from thrombospondin-1 inhibited H2S-induced activation, whereas two other functional sequences from thrombospondin-1 enhanced H2S signaling. Therefore, engaging CD47 is necessary and sufficient for thrombospondin-1 to inhibit H2S-dependent T cell activation. H2S stimulated T cell activation by potentiating MEK-dependent ERK phosphorylation, and thrombospondin-1 inhibited this signaling in a CD47-dependent manner. Thrombospondin-1 also limited activation-dependent T cell expression of the H2S biosynthetic enzymes cystathionine beta-synthase and cystathionine gamma-lyase, thereby limiting the autocrine role of H2S in T cell activation. Thus, thrombospondin-1 signaling through CD47 is the first identified endogenous inhibitor of H2S signaling and constitutes a novel mechanism that negatively regulates T cell activation. |