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

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

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)

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.

Original languageEnglish
Article numbere149301
Pages (from-to)e149301
Number of pages12
JournalJCI Insight
Volume6
Issue number18
Early online date10 Aug 2021
DOIs
Publication statusPublished - 22 Sept 2021

Keywords

  • Nox2
  • Heart transplant
  • Regulatory T cells
  • miR214-3p
  • Chemotaxis

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