Programmed Death-Ligand 2 Deficiency Exacerbates Experimental Autoimmune Myocarditis in Mice.

Siqi Li,Kazutaka Aonuma,Yuzuno Shimoda,Dongzhu Xu,Zoughu Song,Honglan Huang,Kazuko Tajiri,Keiko Inoue,Kazuhiro Aonuma,Duo Feng,Masaki Ieda,Zixun Yuan,Haruka Mori,Saori Yonebayashi,Nobuyuki Murakoshi,Yuta Okabe

doi:10.3390/ijms22031426

Abstract

Programmed death ligand 2 (PD-L2) is the second ligand of programmed death 1 (PD-1) protein. In autoimmune myocarditis, the protective roles of PD-1 and its first ligand programmed death ligand 1 (PD-L1) have been well documented; however, the role of PD-L2 remains unknown. In this study, we report that PD-L2 deficiency exacerbates myocardial inflammation in mice with experimental autoimmune myocarditis (EAM). EAM was established in wild-type (WT) and PD-L2-deficient mice by immunization with murine cardiac myosin peptide. We found that PD-L2-deficient mice had more serious inflammatory infiltration in the heart and a significantly higher myocarditis severity score than WT mice. PD-L2-deficient dendritic cells (DCs) enhanced CD4+ T cell proliferation in the presence of T cell receptor and CD28 signaling. These data suggest that PD-L2 on DCs protects against autoreactive CD4+ T cell expansion and severe inflammation in mice with EAM.

Highlights

We investigated the effect of Programmed death ligand 2 (PD-L2) deficiency on the development of myocarditis in the experimental autoimmune myocarditis (EAM) model
We found that PD-L2 deficiency caused severe inflammaistration of anti-programmed death 1 (PD-1) antibodies exacerbated cardiac myosin peptide-induced experimental autoimmune myocarditis (EAM) [9]
We examined the functional significance of PD-L2 in EAM

Summary

Introduction

The programmed cell death protein 1 (PD-1) pathway has been shown to be an attractive target for cancer immunotherapy. Immune checkpoint inhibitors targeting PD1 or one of its ligands such as the programmed cell death ligand 1 (PD-L1) improves the prognosis of various malignancies [1,2]. Myocarditis is a relatively rare, but potentially lifethreatening cardiovascular side effect; it has become an emergent problem for clinicians in their daily routines [2,3]. Given these clinical aspects, a better understanding of how disruption of this pathway influences the immune system in the heart is needed

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