Mitochondrial deacetylase Sirt3 plays an important role in donor T cell responses after experimental allogeneic hematopoietic transplantation

• Verfasst von: Toubai, Tomomi [VerfasserIn]
• Verfasst von: Rossi, Corinne [VerfasserIn]
• Titel: Mitochondrial deacetylase Sirt3 plays an important role in donor T cell responses after experimental allogeneic hematopoietic transplantation
• Verf.angabe: Tomomi Toubai, Hiroya Tamaki, Daniel C. Peltier, Corinne Rossi, Katherine Oravecz-Wilson, Chen Liu, Cynthia Zajac, Julia Wu, Yaping Sun, Hideaki Fujiwara, Israel Henig, Stephanie Kim, David B. Lombard, and Pavan Reddy
• E-Jahr: 2018
• Jahr: August 28, 2018
• Umfang: 13 S.
• Fussnoten: Gesehen am 30.04.2019
• Titel Quelle: Enthalten in: The journal of immunology
• Ort Quelle: Bethesda, Md. : Soc., 1916
• Jahr Quelle: 2018
• Band/Heft Quelle: 201(2018), 11, Seite 3443-3455
• ISSN Quelle: 1550-6606
• DOI: doi:10.4049/jimmunol.1800148
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1663839328

Abstract

Allogeneic hematopoietic cell transplantation (allo-HCT) through its graft-versus-tumor (GVT) effects is a curative therapy against many hematological malignancies. However, GVT is linked to harmful graft-versus-host disease (GVHD) after allo-HCT. Both GVT and GVHD require allogeneic T cell responses, which is an energetically costly process that causes oxidative stress. Sirtuin 3 (SIRT3), a mitochondrial histone deacetylase (HDAC), plays an important role in cellular processes through inhibition of reactive oxygen species (ROS). Nonmitochondrial class of HDACs regulate T cell responses, but the role of mitochondrial HDACs, specifically SIRT3, on donor T cell responses after allo-HCT remains unknown. In this study, we report that SIRT3-deficient (SIRT3−/−) donor T cells cause reduced GVHD severity in multiple clinically relevant murine models. The GVHD protective effect of allogeneic SIRT3−/− T cells was associated with a reduction in their activation, reduced CXCR3 expression, and no significant impact on cytokine secretion or cytotoxic functions. Intriguingly, the GVHD protective effect of SIRT3−/− T cells was associated with a reduction in ROS production, which is contrary to the effect of SIRT3 deficiency on ROS production in other cells/tissues and likely a consequence of their deficient activation. Notably, the reduction in GVHD in the gastrointestinal tract was not associated with a substantial reduction in the GVT effect. Collectively, these data reveal that SIRT3 activity promotes allogeneic donor T cell responses and ROS production without altering T cell cytokine or cytolytic functions and identify SIRT3 as a novel target on donor T cells to improve outcomes after allo-HCT.