The Proatherogenic Role of T Cells Requires Cell Division and Is Dependent on the Stage of the Disease

Abstract

Objective— The mechanism by which T cells exert a proatherogenic potential is unclear. In order to determine whether this potential requires their replication, we crossed atherosclerosis-prone apolipoprotein E knockout mice (ApoE°) with transgenic mice in which exclusive and conditional ablation of dividing T cells relies on their specific expression of the herpes simplex type 1 thymidine kinase (TK) suicide gene. Methods and Results— We first showed that conalbumin-immunized ApoE°TK mice mounted a significant immune response to the antigen that was fully and specifically blocked by an in vivo ganciclovir (GCV) treatment. Next, ApoE°TK mice and ApoE° mice were treated or not with GCV either during the first 4 weeks (GCV 1 to 4w), the last 4 weeks (GCV 5 to 8w), or during 8 weeks (GCV 1 to 8w). Strikingly, ApoE°TK mice displayed a dramatic decrease in lesion development in the GCV 1 to 8w and GCV 5 to 8w groups, whereas the GCV had no effect when administered during the first 4 weeks. In protected mice, the inflammatory parameters in lesions, the percentage of CD69 + CD3 + splenocytes, and the circulating natural killer T cells were reduced. Conclusions— The present study, therefore, shows that the proatherogenic potential of T cells is crucial in the progression of fatty streaks to mature plaques and requires cell division.