CD47-dependent regulation of H₂S biosynthesis and signaling in T cells.
Pharmacological concentrations of H2S donors inhibit some T cell functions by inhibiting mitochondrial function, but evidence is also emerging that H2S at physiological concentrations produced via chemical sources and endogenously is a positive physiological mediator of T cell function. Expression of the H2S biosynthetic enzymes cystathionine γ-lyase (CSE) and cystathionine β-synthase (CBS) is induced in response to T cell receptor signaling. Inhibiting the induction of these enzymes limits T cell activation and proliferation, which can be overcome by exposure to exogenous H2S at submicromolar concentrations. Exogenous H2S at physiological concentrations increases the ability of T cells to form an immunological synapse by altering cytoskeletal actin dynamics and increasing the reorientation of the microtubule-organizing center. Downstream, H2S enhances T cell receptor-dependent induction of CD69, CD25, and Interleukin-2 (IL-2) gene expression. The T cell stimulatory activity of H2S is enhanced under hypoxic conditions that limit its oxidative metabolism by mitochondrial and nonenzymatic processes. Studies of the receptor CD47 have revealed the first endogenous inhibitory signaling pathway that regulates H2S signaling in T cells. Binding of the secreted protein thrombospondin-1 to CD47 elicits signals that block the stimulatory activity of exogenous H2S on T cell activation and limit the induction of CSE and CBS gene expression. CD47 signaling thereby inhibits T cell receptor-mediated T cell activation.
Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Sukhbir
S
Kaur
Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Anthony L
AL
Schwartz
Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Thomas W
TW
Miller
Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. Electronic address: droberts@helix.nih.gov.
David D
DD
Roberts
D058186:Acute Kidney Injury / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism / Q000494:pharmacology*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001249:Asthma / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051928:CD47 Antigen / Q000235:genetics* / Q000276:immunology; D002448:Cell Adhesion / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003541:Cystathionine beta-Synthase / Q000235:genetics / Q000378:metabolism; D003542:Cystathionine gamma-Lyase / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D006862:Hydrogen Sulfide / Q000378:metabolism / Q000494:pharmacology*; D007111:Immunity, Cellular; D054992:Immunological Synapses / Q000187:drug effects; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects; D011565:Psoriasis / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019700:Thrombospondin 1 / Q000235:genetics / Q000276:immunology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D051928:CD47 Antigen; D019700:Thrombospondin 1; D003541:Cystathionine beta-Synthase; D003542:Cystathionine gamma-Lyase; D006862:Hydrogen Sulfide
CD47; Cystathionine β-synthase; Cystathionine γ-lyase; Hydrogen sulfide; Inflammation; T-cell activation; T-cell receptor; Thrombospondin-1