Stimulation of the PD-1 Pathway Decreases Atherosclerotic Lesion Development in Ldlr Deficient Mice

Abstract

Aim: Signaling through the coinhibitory programmed death (PD)-1/PD-L1 pathway regulates T cell responses and can inhibit ongoing immune responses. Inflammation is a key process in the development of atherosclerosis, the underlying cause for the majority of cardiovascular diseases. Dampening the excessive immune response that occurs during atherosclerosis progression by promoting PD-1/PD-L1 signaling may have a high therapeutic potential to limit disease burden. In this study we therefore aimed to assess whether an agonistic PD-1 antibody can diminish atherosclerosis development.Methods and Results: Ldlr−/− mice were fed a western-type diet (WTD) while receiving 100 μg of an agonistic PD-1 antibody or control vehicle twice a week. Stimulation of the PD-1 pathway delayed the WTD-induced monocyte increase in the circulation up to 3 weeks and reduced T cell activation and proliferation. CD4+ T cell numbers in the atherosclerotic plaque were reduced upon PD-1 treatment. More specifically, we observed a 23% decrease in atherogenic IFNγ-producing splenic CD4+ T cells and a 20% decrease in cytotoxic CD8+ T cells, whereas atheroprotective IL-10 producing CD4+ T cells were increased with 47%. Furthermore, we found an increase in regulatory B cells, B1 cells and associated atheroprotective circulating oxLDL-specific IgM levels in agonistic PD-1-treated mice. This dampened immune activation following agonistic PD-1 treatment resulted in reduced atherosclerosis development (p < 0.05).Conclusions: Our data show that stimulation of the coinhibitory PD-1 pathway inhibits atherosclerosis development by modulation of T- and B cell responses. These data support stimulation of coinhibitory pathways as a potential therapeutic strategy to combat atherosclerosis.

IFNγ-Stimulated B Cells Inhibit T Follicular Helper Cells and Protect Against Atherosclerosis

“…Mice deficient in both PD-L1 and PD-L2 show increased atherosclerosis (25). Similarly, PD-1 knockout mice or mice treated with a PD-1 blocking antibody developed exacerbated atherosclerosis (26,27), whereas stimulation of PD-1 signaling reduces atherosclerosis (28). Our data is further supported by previous studies that demonstrated the proatherogenic role of T FH cells (12)(13)(14).…”

Cardiovascular Monitoring of Cancer Patients Undergoing Immune Checkpoint Inhibitor Therapy: Preliminary Results from a Prospective Observational Study

“…Previously the association between ICI and the progression of atherosclerosis has been highlighted (9,13). In our study, we observed an increase in the percentage of patients with atherosclerotic lesions in the common carotid artery after 3 months.…”

T cell specific deletion of Casitas B lineage lymphoma-b reduces atherosclerosis, but increases plaque T cell infiltration and systemic T cell activation

“…Exhausted T cells lose some of their effector functions, and thereby potentially also their pro-atherogenic role. For example, stimulation of the main immune checkpoint for T cell exhaustion, PD-1, decreases the formation of atherosclerotic lesions in mice by reducing T cell activation and proliferation ( 51 ). Moreover, Bazioti et al.…”