Chapter Eight – CD47-Dependent Regulation of H2S Biosynthesis and Signaling in T Cells

Abstract Pharmacological concentrations of H 2 S donors inhibit some T cell functions by inhibiting mitochondrial function, but evidence is also emerging that H 2 S at physiological concentrations produced via chemical sources and endogenously is a positive physiological mediator of T cell function. Expression of the H 2 S 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 H 2 S at submicromolar concentrations. Exogenous H 2 S 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, H 2 S enhances T cell receptor-dependent induction of CD69 , CD25 , and Interleukin-2 (IL-2) gene expression. The T cell stimulatory activity of H 2 S 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 H 2 S signaling in T cells. Binding of the secreted protein thrombospondin-1 to CD47 elicits signals that block the stimulatory activity of exogenous H 2 S 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.