title: Thrombospondin-1 is a CD47-dependent endogenous inhibitor of hydrogen sulfide signaling in T cell activation.
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 β-synthase and cystathionine γ-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.
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Miller
authors.forename: Sukhbir
authors.initials: S
authors.lastname: Kaur
authors.forename: Kelly
authors.initials: K
authors.lastname: Ivins-O'Keefe
authors.forename: David D
authors.initials: DD
authors.lastname: Roberts
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D051928:CD47 Antigen / Q000235:genetics / Q000378:metabolism*; D003541:Cystathionine beta-Synthase / Q000235:genetics / Q000378:metabolism; D003542:Cystathionine gamma-Lyase / Q000235:genetics / Q000378:metabolism; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D006862:Hydrogen Sulfide / Q000378:metabolism* / Q000494:pharmacology; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D061251:Primary Cell Culture; D011485:Protein Binding; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D019700:Thrombospondin 1 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D051928:CD47 Antigen; D003541:Cystathionine beta-Synthase; D003542:Cystathionine gamma-Lyase; D005353:Fibronectins; D006862:Hydrogen Sulfide; D007376:Interleukin-2; D037181:Lectins, C-Type; D019700:Thrombospondin 1; D000099192:CD69 Antigens; C497895:Cd47 protein, mouse; C585483:Thbs1 protein, mouse
keywords: CBS; CD47; CSE; ERK; Extracellular signal-regulated kinase; Extracellular signal-regulated kinases; Hydrogen sulfide; IL-2; Interleukin-2; MEK; Mitogen-activated protein kinase kinase; Redox signaling; T cell antigen receptor; T lymphocytes; TCR; TSP1; Thrombospondin-1; cystathionine β-synthase; cystathionine γ-lyase