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Nox2-deficient Tregs improve heart transplant outcomes via their increased graft recruitment and enhanced potency: Nox2-deficient Tregs improve heart allograft outcome

Research output: Contribution to journalArticlepeer-review

Silvia Cellone Trevelin, Anna Zampetaki, Greta Sawyer, Alex Ivetic, Alison Brewer, Lesley A. Smith, Federica M. Marelli-Berg, Robert Köchl, Robert I. Lechler, Ajay Shah, Giovanna Lombardi

Original languageEnglish
Article numbere149301
Pages (from-to)e149301
Number of pages12
JournalJCI Insight
Volume6
Issue number18
Early online date10 Aug 2021
DOIs
E-pub ahead of print10 Aug 2021
Published22 Sep 2021

Bibliographical note

Funding Information: We thank Ioannis Smyrnias for assistance with the histological analyses; Kulachelvy Ratnasothy, Rose-Marie Minaisah, Richard Thompson, Xiahong Zhang, Sadia Ahmad, and Ana Georgian for general technical assistance; and Norman Catibog for assistance with the echocardiography videos. This study was supported by the British Heart Foundation (PG/18/43/33688; RE/18/2/34213; CH/1999001/11735) and the Department of Health via the National Institute for Health Research Biomedical Research Centre, awarded to Guy’s & St. Thomas’ NHS Foundation Trust in partnership with King’s College London and King’s College Hospital NHS Foundation Trust (IS-BRC-1215-20006). Address correspondence to: Giovanna Lombardi, Immunoregulation laboratory, MRC Centre for Transplantation, 5th Floor Tower Wing, Guy’s Hospital, London SE1 9RT, United Kingdom. Phone: 0207.1887674; Email: giovanna.lombardi@kcl.ac.uk. Or to: Ajay M. Shah, James Black Centre, 125 Coldharbour Lane, London SE5 9NU, United Kingdom. Phone: 44.0.20.7848.5189; Email: ajay.shah@kcl.ac.uk. Publisher Copyright: © 2021, Trevelin et al. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

King's Authors

Abstract

Nox2 is a ROS-generating enzyme, deficiency of which increases suppression by Tregs in vitro and in an in vivo model of cardiac remodeling. As Tregs have emerged as a candidate therapy in autoimmunity and transplantation, we hypothesized that Nox2 deficiency in Tregs in recipient mice may improve outcomes in a heart transplant model. We generated a potentially novel B6129 mouse model with Treg-targeted Nox2 deletion (Nox2 fl/flFoxP3Cre + mice) and transplanted with hearts from CB6F1 donors. As compared with those of littermate controls, Nox2 fl/flFoxP3Cre+ mice had lower plasma levels of alloantibodies and troponin-I, reduced levels of IFN-γ in heart allograft homogenates, and diminished cardiomyocyte necrosis and allograft fibrosis. Single-cell analyses of allografts revealed higher absolute numbers of Tregs and lower CD8+ T cell infiltration in Nox2-deficient recipients compared with Nox2-replete mice. Mechanistically, in addition to a greater suppression of CD8+CD25– T effector cell proliferation and IFN-γ production, Nox2-deficient Tregs expressed higher levels of CCR4 and CCR8, driving cell migration to allografts; this was associated with increased expression of miR-214-3p. These data indicate that Nox2 deletion in Tregs enhances their suppressive ability and migration to heart allografts. Therefore, Nox2 inhibition in Tregs may be a useful approach to improve their therapeutic efficacy.

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