Thrombospondin-1 is a CD47-dependent endogenous inhibitor of hydrogen sulfide signaling in T cell activation

详细信息    查看全文

• 作者：Thomas W. Miller ; Sukhbir Kaur ; Kelly Ivins-O'Keefe ; David D. Roberts
• 关键词：CBS ; cystathionine ¦Â-synthase ; CSE ; cystathionine ¦Ã-lyase ; ERK ; Extracellular signal-regulated kinases ; IL-2 ; Interleukin-2 ; MEK ; Mitogen-activated protein kinase kinase ; TCR ; T cell antigen receptor ; TSP1 ; Thrombospondin-1
• 刊名：Matrix Biology
• 出版年：2013
• 出版时间：8 August, 2013
• 年：2013
• 卷：32
• 期：6
• 页码：316-324
• 全文大小：584 K

文摘

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 ¦Â-synthase and cystathionine ¦Ã-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.