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.

Background: Several Epidermal Growth Factor receptor (EGFR) inhibitors have been successfully developed for the treatment of cancer. They inhibit tumor cell survival, proliferation and migration. EGFR is also expressed by leukocytes, but little is known about its role in the modulation of the immune response. We aimed to determine whether EGF-R expressed on CD4 + T cells is functional, and to address the consequences of EGF-R inhibition in atherosclerosis, a T cell-mediated chronic inflammatory disease of the vascular wall. Method and 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 for 8 weeks induced T cell anergy, reduced T cell infiltration within atherosclerotic lesions and protected against atherosclerosis. 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 IFN-γ, IL-17A, IL-4 and IL-10 production. Atherosclerotic lesion size was reduced by 2-fold in irradiated Ldlr -/- mice reconstituted with bone marrow from Cd4Cre Egfr lox/lox mouse, compared to Cd4Cre Egfr +/+ chimeric mice, after 4, 6 and 12 weeks of high fat diet, associated with marked reduction in T cell infiltration in atherosclerotic plaques. Finally, human blood T cells expressed EGFR and EGFR inhibition reduced T cell proliferation both in vivo and in vitro . Conclusion: EGFR is expressed by human and mouse CD4 + T cells. EGFR pharmacological inhibition or genetic invalidation induced T cell anergy in vitro and in vivo , and reduced atherosclerosis development. Our results suggest that targeting EGFR may be a novel strategy to combat atherosclerosis.