KLF10 deficiency in CD4+ T cells promotes atherosclerosis progression by altering macrophage dynamics

Atherosclerosis. 2022 Oct;359:27-41. doi: 10.1016/j.atherosclerosis.2022.08.019. Epub 2022 Sep 13.

Abstract

Background and aims: Accumulating evidence supports a critical role for CD4+ T cells as drivers and modifiers of the chronic inflammatory response in atherosclerosis. Effector T cells have pro-atherogenic properties, whereas CD4+ regulatory T cells (Tregs) exert suppressive activity in atherosclerosis through increased secretion of inhibitory cytokines such as transforming growth factor-β or interleukin-10. In addition, Tregs have been shown to suppress inflammatory macrophages and promote the resolution of atherosclerosis plaques. Impaired Treg numbers and function have been associated with atherosclerosis plaque development. However, the underlying mechanisms remain unclear.

Methods and results: Here, we investigated a cell-autonomous role of a transcription factor, Krüppel-like factor 10 (KLF10), in CD4+ T cells in regulating atherosclerosis progression. Using CD4+ T-cell-specific KLF10 knockout (TKO) mice, we identified exaggerated plaque progression due to defects in immunosuppressive functions of Tregs on macrophages. TKO mice exhibited increased lesion size as well as higher CD4+ T cells and macrophage content compared to WT mice. TKO plaques also showed increased necrotic cores along with defective macrophage efferocytosis. In contrast, adoptive cellular therapy using WT Tregs abrogated the accelerated lesion progression and deleterious effects in TKO mice. Intriguingly, RNA-seq analyses of TKO lesions revealed increased chemotaxis and cell proliferation, and reduced phagocytosis compared to WT lesions. Mechanistically, TKO-Tregs impaired the efferocytosis capacity of macrophages in vitro and promoted a pro-inflammatory macrophage phenotype via increased IFN-γ and decreased TGF-β secretion.

Conclusions: Taken together, these findings establish a critical role for KLF10 in regulating CD4+ Treg-macrophage interactions and atherosclerosis.

Keywords: Atherosclerosis; CD4(+) T cell; Inflammation; KLF10; Macrophage; Treg.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atherosclerosis* / genetics
  • Atherosclerosis* / pathology
  • CD4-Positive T-Lymphocytes
  • Cytokines
  • Early Growth Response Transcription Factors
  • Factor X
  • Interleukin-10
  • Kruppel-Like Transcription Factors / genetics
  • Macrophages / pathology
  • Mice
  • Mice, Inbred C57BL
  • Plaque, Atherosclerotic*
  • T-Lymphocytes, Regulatory
  • Transforming Growth Factor beta
  • Transforming Growth Factors

Substances

  • Cytokines
  • Early Growth Response Transcription Factors
  • KLF10 protein, mouse
  • Kruppel-Like Transcription Factors
  • Transforming Growth Factor beta
  • Interleukin-10
  • Transforming Growth Factors
  • Factor X