Blood Journal
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Transplant tolerance is associated with reduced expression of cystathionine-γ-lyase that controls IL-12 production by dendritic cells and TH-1 immune responses

  1. Romain Vuillefroy de Silly1,2,
  2. Flora Coulon1,2,
  3. Nicolas Poirier1,2,
  4. Vojislav Jovanovic1,
  5. Sophie Brouard1,
  6. Véronique Ferchaud-Roucher2,3,
  7. Gilles Blancho1,2, and
  8. Bernard Vanhove1,2
  1. 1Inserm, Unité Mixte de Recherche-S1064, Institut de Transplantation Urologie Nephrologie, Nantes, France;
  2. 2Université de Nantes, Centre Hospitalier Universitaire de Nantes, Nantes, France; and
  3. 3Inserm, Unité Mixte de Recherche 915, Nantes, France

Abstract

Antigen-activated T lymphocytes undergo an immune or tolerogeneic response in part according to the activation status of their antigen-presenting cells. However, factors controlling the activation of antigen-presenting cells are not fully understood. In this study, we demonstrate that immune tolerance after organ allotransplantation in the rat is associated with a repressed intragraft expression of several enzymes of the trans-sulfuration pathway, including cystathionine γ-lyase (CSE). The pharmacologic blockade of CSE with propargylglycine delayed heart allograft rejection and abrogated type IV hypersensitivity but did not modify antibody responses, and was associated with a selective inhibition of the TH-1 type factors T-bet, IL-12, and IFN-γ. IL-12 repression could also be induced by propargylglycine in vitro in monocytes and dendritic cells (DCs), a phenomenon not mediated by changes to nuclear factor-κ B or hydrogen sulfide but that occurred together with a modulation of intracellular cysteine content. Intracellular cysteine levels were predominantly controlled in DCs by CSE activity, together with extracellular import via the Xc transporter. Our results indicate that CSE plays a critical role in regulating IL-12 in monocytes and DCs and is down-modulated in transplant tolerance, presumably participating in the maintenance of the tolerant state.

  • Submitted April 21, 2011.
  • Accepted January 15, 2012.
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