Impairment of the programmed cell death-1 pathway increases atherosclerotic lesion development and inflammation

Area of Science:

• Immunology
• Cardiovascular Research
• Cell Biology

Background:

• Programmed cell death-1 (PD-1) is a receptor that inhibits T-cell activity upon binding its ligands, PD-L1 and PD-L2.
• The PD-1 pathway plays a role in immune system regulation, preventing excessive immune responses.

Purpose of the Study:

• To investigate the role of the PD-1 pathway in regulating T cells involved in atherosclerotic lesion formation and inflammation.
• To determine the impact of PD-1 pathway deficiency or blockade on the development of atherosclerosis.

Main Methods:

• Utilized genetically modified mouse models (Pd1-/-Ldlr-/- and Ldlr-/-) to study atherosclerosis.
• Administered anti-PD-1 blocking antibodies to hypercholesterolemic mice.
• Analyzed atherosclerotic lesion size, immune cell infiltration (T cells, macrophages), and serum inflammatory markers.
• Assessed T-cell proliferation, cytotoxic activity, and activation status in vitro and in vivo.
• Employed bone marrow chimeric mice to investigate the role of PD-1 ligands on hematopoietic cells.

Main Results:

• Mice lacking PD-1 (Pd1-/-Ldlr-/-) exhibited larger atherosclerotic lesions with increased CD4+ and CD8+ T cells and macrophages.
• PD-1 deficient mice showed elevated serum tumor necrosis factor-α levels.
• T cells from Pd1-/-Ldlr-/- mice demonstrated enhanced proliferation and CD8+ T-cell cytotoxicity.
• Blocking PD-1 in hypercholesterolemic mice led to increased lesional inflammation, T-cell infiltration, and activation.
• Similar effects were observed in chimeric mice lacking PD-L1 and PD-L2 on hematopoietic cells.

Conclusions:

• The PD-1 pathway is crucial in suppressing proatherogenic T-cell responses.
• Therapeutic blockade of PD-1, while beneficial for cancer or infections, may elevate the risk of cardiovascular complications due to enhanced atherosclerosis.