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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:353.)
© 2006 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

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

Jamila Khallou-Laschet; Giuseppina Caligiuri; Emilie Groyer; Emanuel Tupin; Anh-Thu Gaston; Bruno Poirier; Mitchell Kronenberg; José L. Cohen; David Klatzmann; Srini V. Kaveri; Antonino Nicoletti

From the INSERM U681 (J.K-L., G.C., E.G., E.T., A-T.G., B.P., S.V.K., A.N.), Institut des Cordeliers/Université Paris 6 UPMC, Paris, France; Division of Developmental Immunology (E.T., M.K.), La Jolla Institute for Allergy and Immunology, San Diego, Calif; and Centre National de la Recherche Scientifique–Unité Mixte de Recherche 7087 (J.L.C., D.K.), Hôpital Pitié-Salpétrière, Paris, France.

Correspondence to Antonino Nicoletti, INSERM U681, Institut des Cordeliers, 15, rue de l’Ecole de Médicine, Paris, France. E-mail antonino.nicoletti{at}upmc.fr

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.

Atherosclerosis-prone ApoE°TK mice in which targeted ablation of dividing T cells can be achieved were used to show that the proatherogenic potential of T cells is crucial in the progression from fatty streaks to mature plaques and requires cell division.

Key Words: immune response • NKT lymphocytes • regulatory T cells • thymidine kinase

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