Journal Article

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

Shah, Ajay M., Lombardi, Giovanna, Köchl, Robert, Lechler, Robert I., Sawyer, Greta, Zampetaki, Anna, Trevelin, Silvia C., Brewer, Alison C., Smyth, Lesley Ann, Marelli-Berg, Federica, Ivetic, Aleksandar

2021

Overview

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 (Nox2fl/flFoxP3Cre+ mice) and transplanted with hearts from CB6F1 donors. As compared with those of 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 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.

• Publisher: American Society for Clinical Investigation,American Society for Clinical investigation
• Subject: Alloantibodies / Allografts / Allografts - immunology / Allografts - metabolism / Allografts - pathology / Animals / Autoimmunity / Cardiology / Cardiomyocytes / CD25 antigen / CD8 antigen / CD8-Positive T-Lymphocytes - physiology / Cell migration / Cell Movement / Cell Proliferation / CYBB protein / Female / Fibrosis / Gene deletion / Graft Rejection - blood / Graft Rejection - immunology / Heart Transplantation / Heart transplants / Immunology / Interferon-gamma - metabolism / Isoantibodies - blood / Liver transplants / Lymphatic system / Lymphocytes / Lymphocytes T / Male / Mice / Mice, Knockout / MicroRNAs - metabolism / Myocytes, Cardiac - pathology / NADPH Oxidase 2 - genetics / Necrosis / Plasma / Plasma levels / Receptors, CCR4 - metabolism / Receptors, CCR8 - metabolism / Surgery / T-Lymphocytes, Regulatory - immunology / T-Lymphocytes, Regulatory - metabolism / Thymus gland / Transplantation, Homologous / Troponin / Troponin I - blood / γ-Interferon