IL-2Rβγ signalling in lymphocytes promotes systemic inflammation and reduces plasma cholesterol in atherosclerotic mice

Atherosclerosis. 2021 Jun:326:1-10. doi: 10.1016/j.atherosclerosis.2021.04.010. Epub 2021 Apr 24.


Background and aims: The relationship between inflammation and lipid metabolism is complex and bidirectional. Lymphocyte-driven inflammation has been shown to modulate both atherosclerotic plaque development and cholesterol levels, but the mechanisms are incompletely understood.

Methods: The cardiometabolic effects of IL-2Rβγ signalling in atherosclerotic Apoe-/- mice were investigated by treatment with an agonistic IL-2Rβγ-targeting IL-2/anti-IL-2 complex or a monoclonal anti-CD122 (IL-2Rβ) blocking antibody.

Results: Administration of IL-2Rβγ agonistic IL-2/anti-IL-2 complexes to Apoe-/- mice augmented opposing arms of the adaptive immune system. Expansion of effector/memory T cells and increased levels of circulating pro-inflammatory cytokines were observed along with elevated levels of regulatory T cells and IL-10. Notably, IL-2/anti-IL-2 treatment did not affect plaque size but decreased levels of plasma cholesterol. The cholesterol lowering effect of IL-2Rβγ agonism was not affected by anti-CD8 or anti-NK1.1 depleting antibody treatment but was contingent on the presence of adaptive immunity. Expression of multiple liver X receptor (LXR)-related genes, including Pltp and Srebp1c in the liver, was decreased by IL-2/anti-IL-2 treatment. Although IL-2Rβγ agonism lowered cholesterol levels, blocking IL-2Rβγ signalling using an anti-CD122 monoclonal antibody did not impact cholesterol levels or plaque burden in Apoe-/- mice.

Conclusions: Elevated IL-2Rβγ signalling results in activation of both inflammatory and regulatory lymphocytes with a net zero effect on atherosclerosis and decreased plasma cholesterol levels. Changes in cholesterol levels were associated with reductions in hepatic LXR-related gene expression. Further studies are needed to investigate the clinical significance of IL-2 mediated modulation of hepatic LXR signalling in inflammatory disorders.

Keywords: Atherosclerosis; Cholesterol; Cytokines; IL-2; Inflammation; T cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atherosclerosis*
  • Cholesterol
  • Inflammation
  • Interleukin-2 Receptor beta Subunit*
  • Lymphocytes
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout, ApoE
  • Plaque, Atherosclerotic*


  • Il2rb protein, mouse
  • Interleukin-2 Receptor beta Subunit
  • Cholesterol