Programmed Death Ligand 1 Regulates a Critical Checkpoint for Autoimmune Myocarditis and Pneumonitis in MRL Mice

Abstract

MRL/MpJ-Faslpr (MRL-Faslpr) mice develop a spontaneous T cell and macrophage-dependent autoimmune disease that shares features with human lupus. Interactions via the programmed death 1/programmed death ligand 1 (PD-1/PD-L1) pathway down-regulate immune responses and provide a negative regulatory checkpoint in mediating tolerance and autoimmune disease. Therefore, we tested the hypothesis that the PD-1/PD-L1 pathway suppresses lupus nephritis and the systemic illness in MRL-Faslpr mice. For this purpose, we compared kidney and systemic illness (lymph nodes, spleen, skin, lung, glands) in PD-L1 null (−/−) and PD-L1 intact (wild type, WT) MRL-Faslpr mice. Unexpectedly, PD-L1−/−;MRL-Faslpr mice died as a result of autoimmune myocarditis and pneumonitis before developing renal disease or the systemic illness. Dense infiltrates, consisting of macrophage and T cells (CD8+ > CD4+), were prominent throughout the heart (atria and ventricles) and localized specifically around vessels in the lung. In addition, once disease was evident, we detected heart specific autoantibodies in PD-L1−/−;MRL-Faslpr mice. This unique phenotype is dependent on MRL-specific background genes as PD-L1−/−;MRL+/+ mice lacking the Faslpr mutation developed autoimmune myocarditis and pneumonitis. Notably, the transfer of PD-L1−/−;MRL+/+ bone marrow cells induced myocarditis and pneumonitis in WT;MRL+/+ mice, despite a dramatic up-regulation of PD-L1 expression on endothelial cells in the heart and lung of WT;MRL+/+ mice. Taken together, we suggest that PD-L1 expression is central to autoimmune heart and lung disease in lupus-susceptible (MRL) mice.

Reciprocal differentiation and tissue-specific pathogenesis of Th1, Th2, and Th17 cells in graft-versus-host disease

“…This is consistent with reports that tissue expression of B7-H1 tolerize infiltrating T cells in the lung and other peripheral organs. 46,47 This finding provides a likely answer to questions brought up by Burman and colleagues regarding an IFN-␥-induced unknown protective mechanism possessed by the host tissues. 21 Furthermore, we observed that all GVHD target tissues could up-regulate expression of B7-H1 in an IFN-␥-dependent manner and that tissue expression of B7-H1 also played an important role in ameliorating Th1-mediated GVHD tissue damage in gut and liver (Yi T, Zeng D, unpublished observation).…”

Expression of coinhibitory PD-L1 on CD4+CD25+FOXP3+ regulatory T cells is elevated in patients with acute coronary syndrome

“…In previous studies, PD-L1 chimeric mice that expressed PD-L1 only on hematopoietic cells of the heart showed an accelerated, early graft rejection after heart transplantation, whereas the expression of PD-L1 on non-hematopoietic cells of the heart led to a delayed rejection. These data indicate that PD-L1 expression on nonhematopoietic cells plays a significant role in regulating transplantation immune responses [14][15][16].…”

Human decidual macrophages suppress IFN-γ production by T cells through costimulatory B7-H1:PD-1 signaling in early pregnancy

“…B7-H1 and B7-DC act as inhibitory costimulatory ligands by binding to their common receptor, programmed death-1 (PD-1), which is expressed on activated but not on resting T cells (Freeman et al, 2000). Involvement of the PD-1 pathway in peripheral tolerance is suggested in PD-1-deficient mice that develop a lupus-like autoimmune disease (Nishimura et al, 1999) and autoimmune dilated cardiomyopathy (Lucas et al, 2008).…”