Author + information
- Received April 26, 2017
- Revision received October 15, 2017
- Accepted October 30, 2017
- Published online January 8, 2018.
- Lynda Zeboudj, MSa,b,
- Mikael Maître, MSa,b,
- Lea Guyonnet, PhDa,b,
- Ludivine Laurans, MSa,b,
- Jeremie Joffre, MD, PhDa,b,
- Jeremie Lemarie, MD, PhDa,b,
- Simon Bourcier, MDa,b,
- Wared Nour-Eldine, MSa,b,
- Coralie Guérin, PhDc,
- Jonas Friard, MSd,
- Abdelilah Wakkach, PhDd,
- Elizabeth Fabre, MDe,
- Alain Tedgui, PhDa,b,
- Ziad Mallat, MD, PhDa,b,f,
- Pierre-Louis Tharaux, MD, PhDa,b and
- Hafid Ait-Oufella, MD, PhDa,b,g,∗ ()
- aInserm U970, Paris Cardiovascular Research Center, Paris, France
- bUniversité René Descartes, Paris, France
- cLuxembourg Institute of Health, Department of Infection and Immunity, Strassen, Luxembourg
- dCNRS, LP2M, UMR 7370, Faculté de Médecine, Université de Nice Sophia Antipolis, Nice, France
- eDepartment of Medical Oncology, Hôpital Europeen G. Pompidou, AP-HP, Paris, France
- fDivision of Cardiovascular Medicine, Department of Medicine, University of Cambridge, Cambridge, United Kingdom
- gService de Réanimation Médicale, Hôpital Saint-Antoine, AP-HP, Université Pierre-et-Marie Curie, Paris, France
- ↵∗Address for correspondence:
Dr. Hafid Ait-Oufella, Inserm U970, Paris Cardiovascular Research Center, Université René Descartes, 56, rue Leblanc, Paris 75012, France.
Background 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.
Objectives 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.
Methods The authors used EGFR tyrosine kinase inhibitors (AG-1478, erlotinib) and chimeric Ldlr-/-Cd4-Cre/Egfrlox/lox mouse with a specific deletion of EGFR in CD4+ T cells.
Results 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/Egfrlox/lox 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.
Conclusions 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.
This work was supported by Institut National de Santé et de la Recherche Médicale, research grants ANR-08-EBIO-003 from l'Agence Nationale de la Recherche and from the European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013)/ ERC grant agreement n°107037 (to Dr. Tharaux) and the British Heart Foundation (to Dr. Mallat). The authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Zeboudj and Maître contributed equally to this work. Drs. Ait-Oufella and Tharaux contributed equally to this work.
- Received April 26, 2017.
- Revision received October 15, 2017.
- Accepted October 30, 2017.
- 2018 American College of Cardiology Foundation