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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:671.)
© 2009 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

NKT Cell Subsets Mediate Differential Proatherogenic Effects in ApoE^–/– Mice

Kelly To; Alex Agrotis; Gurdyal Besra; Alex Bobik; Ban-Hock Toh

From the Vascular Biology and Atherosclerosis Laboratory (K.T., A.A., A.B.), Baker IDI Heart and Diabetes Institute, Melbourne, Australia; the School of Biosciences (G.B.), University of Birmingham, Edgbaston, Birmingham, UK; and the Autoimmunity Laboratory (K.T., B.-H.T.), Centre for Inflammatory Diseases, Monash University, Clayton, Australia.

Correspondence to Kelly To, Vascular Biology & Atherosclerosis Laboratory, Baker IDI Heart & Diabetes Institute, PO Box 6492, St Kilda Road Central, Melbourne, Victoria 8008, Australia. E-mail Kelly.To{at}bakeridi.edu.au

Objective— NKT cells promote atherogenesis, but the subtypes responsible have not been identified. We investigated 2 major NKT cell subtypes (CD4⁺ and DN NKT) in ApoE^–/– mice rendered NKT cell–deficient by day-3 neonatal thymectomy (3dTx).

Methods and Results— Atherosclerosis development was studied in thymectomized ApoE^–/– mice fed a high-fat diet with/without adoptively transferred NKT cells. We demonstrate NKT cell deficiency in thymectomized mice and markedly smaller atherosclerotic lesions. The reduction in lesion size was reversed by adoptive transfer of liver-derived NKT cells. Adoptive transfer of CD4⁺, but not DN NKT cells, into 3dTx ApoE^–/– mice increased lesion size 2.5-fold. The differential effects were not attributable to differences in homing to developing atherosclerotic lesions. DN NKT cells expressed at least 3-fold higher levels of inhibitory Ly49 receptors (Ly49A, Ly49C/I, and Ly49G2) than CD4⁺ NKT cells, and lesions expressed large amounts of their MHC class I ligand. In vitro these inhibitory receptors initiated greater effects in DN NKT cells. Culture of each NKT cell subset with TAP-deficient (MHC class I-deficient) dendritic cells and -GalCer led to secretion of similar amounts of proatherogenic cytokines IL-2, IFN-, and TNF but, when cultured with MHC class I–positive dendritic cells, CD4⁺ NKT cells secreted more of these cytokines.

Conclusions— CD4⁺ NKT cells are responsible for the proatherogenic activity of NKT cells. Expression of inhibitory Ly49 receptors by the subtypes appears responsible for regulating their secretion of proatherogenic cytokines and their differential proatherogenic effects.

We examined the role of NKT cell subtypes in atherosclerosis. Adoptive transfer of CD4⁺ but not DN NKT cells into thymectomized NKT cell–deficient ApoE^–/– mice augmented development of atherosclerosis. Activation of inhibitory Ly49 receptors, which are less abundant on CD4⁺ NKT cells, appears responsible for the differential proatherogenic effects.

Key Words: CD4+NKT cells • atherosclerosis • Ly49 • cytokines