Programmed cell death-1 deficiency exacerbates T cell activation and atherogenesis despite expansion of regulatory T cells in atherosclerosis-prone mice

PLoS One. 2014 Apr 1;9(4):e93280. doi: 10.1371/journal.pone.0093280. eCollection 2014.

Abstract

T cell activation represents a double-edged sword in atherogenesis, as it promotes both pro-inflammatory T cell activation and atheroprotective Foxp3(+) regulatory T cell (Treg) responses. Here, we investigated the role of the co-inhibitory receptor programmed cell death-1 (PD-1) in T cell activation and CD4(+) T cell polarization towards pro-atherogenic or atheroprotective responses in mice. Mice deficient for both low density lipoprotein receptor and PD-1 (Ldlr(-/-)Pd1(-/-)) displayed striking increases in systemic CD4(+) and CD8(+) T cell activation after 9 weeks of high fat diet feeding, associated with an expansion of both pro-atherogenic IFNγ-secreting T helper 1 cells and atheroprotective Foxp3+ Tregs. Importantly, PD-1 deficiency did not affect Treg suppressive function in vitro. Notably, PD-1 deficiency exacerbated atherosclerotic lesion growth and entailed a massive infiltration of T cells in atherosclerotic lesions. In addition, aggravated hypercholesterolemia was observed in Ldlr(-/-)Pd1(-/-) mice. In conclusion, we here demonstrate that although disruption of PD-1 signaling enhances both pro- and anti-atherogenic T cell responses in Ldlr(-/-) mice, pro-inflammatory T cell activation prevails and enhances dyslipidemia, vascular inflammation and atherosclerosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atherosclerosis / genetics*
  • Atherosclerosis / immunology*
  • Atherosclerosis / pathology
  • Diet, High-Fat
  • Disease Models, Animal
  • Hypercholesterolemia / genetics
  • Hypercholesterolemia / immunology
  • Immunomodulation / genetics
  • Immunomodulation / immunology
  • Lipids / blood
  • Lymphocyte Activation / genetics*
  • Lymphocyte Activation / immunology*
  • Lymphocyte Count
  • Lymphoid Tissue / immunology
  • Lymphoid Tissue / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Programmed Cell Death 1 Receptor / deficiency*
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism*

Substances

  • Lipids
  • Programmed Cell Death 1 Receptor

Grant support

This work was supported by the Deutsche Forschungsgemeinschaft (SFB1009, project A3, to H.W., and SFB688 project A12 and A22, and FOR809 ZE 827/1-2 to A.Z.) The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. or preparation of the manuscript.