Selective EGF-Receptor Inhibition in CD4 +  T Cells Induces Anergy and Limits Atherosclerosis

Several epidermal growth factor receptor (EGFR) inhibitors have been successfully developed for the treatment of cancer, limiting tumor growth and metastasis. EGFR is also expressed by leukocytes, but little is known about its role in the modulation of the immune response. The aim of this study was...

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Published in:Journal of the American College of Cardiology Vol. 71; no. 2; p. 160
Main Authors: Zeboudj, Lynda, Maître, Mikael, Guyonnet, Lea, Laurans, Ludivine, Joffre, Jeremie, Lemarie, Jeremie, Bourcier, Simon, Nour-Eldine, Wared, Guérin, Coralie, Friard, Jonas, Wakkach, Abdelilah, Fabre, Elizabeth, Tedgui, Alain, Mallat, Ziad, Tharaux, Pierre-Louis, Ait-Oufella, Hafid
Format: Journal Article
Language:English
Published: United States 16.01.2018
Subjects:
Animals
Antineoplastic Agents - pharmacology
Atherosclerosis - immunology
CD4-Positive T-Lymphocytes - immunology
Cytokines - analysis
Cytokines - classification
Cytokines - immunology
ErbB Receptors - antagonists & inhibitors
Erlotinib Hydrochloride - pharmacology
Immunity, Cellular - drug effects
Immunity, Cellular - immunology
Mice
Plaque, Atherosclerotic - drug therapy
Plaque, Atherosclerotic - immunology
Plaque, Atherosclerotic - pathology
Protein Kinase Inhibitors - pharmacology
T-Lymphocytes, Regulatory - immunology
atherosclerosis
immunity
inflammation
lymphocyte
ISSN:1558-3597, 1558-3597
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Summary:Several epidermal growth factor receptor (EGFR) inhibitors have been successfully developed for the treatment of cancer, limiting tumor growth and metastasis. EGFR is also expressed by leukocytes, but little is known about its role in the modulation of the immune response. The aim of this study was to determine whether EGFR expressed on CD4 T cells is functional and to address the consequences of EGFR inhibition in atherosclerosis, a T cell-mediated vascular chronic inflammatory disease. The authors used EGFR tyrosine kinase inhibitors (AG-1478, erlotinib) and chimeric Ldlr Cd4-Cre/Egfr mouse with a specific deletion of EGFR in CD4 T cells. Mouse CD4 T cells expressed EGFR, and the EGFR tyrosine kinase inhibitor AG-1478 blocked in vitro T cell proliferation and Th1/Th2 cytokine production. In vivo, treatment of Ldlr mice with the EGFR inhibitor erlotinib induced T cell anergy, reduced T cell infiltration within atherosclerotic lesions, and protected against atherosclerosis development and progression. Selective deletion of EGFR in CD4 T cells resulted in decreased T cell proliferation and activation both in vitro and in vivo, as well as reduced interferon-γ, interleukin-4, and interleukin-2 production. Atherosclerotic lesion size was reduced by 2-fold in irradiated Ldlr mice reconstituted with bone marrow from Cd4-Cre/Egfr mice, compared to Cd4-Cre/Egfr chimeric mice, after 4, 6, and 12 weeks of high-fat diet, associated with marked reduction in T cell infiltration in atherosclerotic plaques. Human blood T cells expressed EGFR and EGFR inhibition reduced T cell proliferation both in vitro and in vivo. EGFR blockade induced T cell anergy in vitro and in vivo and reduced atherosclerosis development. Targeting EGFR may be a novel strategy to combat atherosclerosis.
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ISSN:1558-3597
1558-3597
DOI:10.1016/j.jacc.2017.10.084