Dendritic Cell KLF2 Expression Regulates T Cell Activation and Proatherogenic Immune Responses

J Immunol. 2016 Dec 15;197(12):4651-4662. doi: 10.4049/jimmunol.1600206. Epub 2016 Nov 11.

Abstract

Dendritic cells (DCs) have been implicated as important regulators of innate and adaptive inflammation in many diseases, including atherosclerosis. However, the molecular mechanisms by which DCs mitigate or promote inflammatory pathogenesis are only partially understood. Previous studies have shown an important anti-inflammatory role for the transcription factor Krüppel-like factor 2 (KLF2) in regulating activation of various cell types that participate in atherosclerotic lesion development, including endothelial cells, macrophages, and T cells. We used a pan-DC, CD11c-specific cre-lox gene knockout mouse model to assess the role of KLF2 in DC activation, function, and control of inflammation in the context of hypercholesterolemia and atherosclerosis. We found that KLF2 deficiency enhanced surface expression of costimulatory molecules CD40 and CD86 in DCs and promoted increased T cell proliferation and apoptosis. Transplant of bone marrow from mice with KLF2-deficient DCs into Ldlr-/- mice aggravated atherosclerosis compared with control mice, most likely due to heightened vascular inflammation evidenced by increased DC presence within lesions, enhanced T cell activation and cytokine production, and increased cell death in atherosclerotic lesions. Taken together, these data indicate that KLF2 governs the degree of DC activation and hence the intensity of proatherogenic T cell responses.

Publication types

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

MeSH terms

  • Animals
  • Atherosclerosis / immunology*
  • Bone Marrow Cells / physiology*
  • Bone Marrow Transplantation
  • Cells, Cultured
  • Cytokines / metabolism
  • Dendritic Cells / physiology*
  • Disease Models, Animal
  • Humans
  • Immunity, Cellular
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / metabolism*
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, LDL / genetics
  • T-Lymphocytes / immunology*

Substances

  • Cytokines
  • Klf2 protein, mouse
  • Kruppel-Like Transcription Factors
  • Receptors, LDL