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

  • Author Footnotes
    1 These authors contributed equally to this work.
    Akm Khyrul Wara
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Shruti Rawal
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Xilan Yang
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA

    Department of General Practice, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, 210031, China
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  • Daniel Pérez-Cremades
    Affiliations
    Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA

    Department of Physiology, University of Valencia, and INCLIVA Biomedical Research Institute, Valencia, 46010, Spain
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  • Madhur Sachan
    Affiliations
    Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
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  • Jingshu Chen
    Affiliations
    Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
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  • Mark W. Feinberg
    Correspondence
    Corresponding author.
    Affiliations
    Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
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  • Author Footnotes
    1 These authors contributed equally to this work.

      Highlights

      • CD4+ Tregs exert suppressive activity on macrophages in atherosclerotic lesions.
      • CD4+ T cell KLF10−/− mice develop increased atherosclerosis and lesional macrophages.
      • Adoptive transfer of WT Tregs but not KO Tregs fully rescued lesion progression.
      • TKO Tregs impaired macrophage efferocytosis in vitro and in vivo.
      • Mechanistically, TKO Tregs promoted a pro-inflammatory macrophage phenotype via IFN-γ.

      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.

      Graphical abstract

      Keywords

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