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

Article


Trevelin, S. C., Zampetaki, A., Sawyer, G., Ivetic, A., Brewer, A. C., Smyth, L. A., Marelli-Berg, F., Köchl, R., Lechler, R. I., Shah, A. M. and Lombardi, G. 2021. Nox2-deficient Tregs improve heart transplant outcomes via their increased graft recruitment and enhanced potency. JCI Insight. https://doi.org/10.1172/jci.insight.149301
AuthorsTrevelin, S. C., Zampetaki, A., Sawyer, G., Ivetic, A., Brewer, A. C., Smyth, L. A., Marelli-Berg, F., Köchl, R., Lechler, R. I., Shah, A. M. and Lombardi, G.
Abstract

Nox2 is a ROS-generating enzyme, deficiency of which increases suppression by Tregs in vitro and in an in vivo model of cardiac remodelling. Since Tregs have emerged as a candidate therapy in autoimmunity and transplantation, we hypothesised that Nox2 deficiency in Tregs in recipient mice may improve outcomes in a heart transplant model. A novel B6129 mouse model with Treg-targeted Nox2 deletion (Nox2ᶠˡ/ᶠˡFoxP3Cre⁺) was generated and transplanted with hearts from CB6F1 donors. As compared to littermate controls, Nox2ᶠˡ/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 to 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 miR214-3p. 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.

Journal JCI Insight
ISSN2379-3708
Year2021
PublisherAmerican Society for Clinical Investigation
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Anyone
Digital Object Identifier (DOI)https://doi.org/10.1172/jci.insight.149301
Publication dates
Online10 Aug 2021
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Deposited17 Aug 2021
Copyright holder© 2021 The Authors
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