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Cutting Edge: CD28 Engagement Releases Antigen-Activated Invariant NKT Cells from the Inhibitory Effects of PD-1¹

Jianxiong Wang^2,*, Lu Cheng^2,*, Zenebech Wondimu, Mark Swain, Pere Santamaria and Yang Yang^3,*

^* Department of Biochemistry and Molecular Biology, Department of Microbiology and Infectious Diseases, and Department of Medicine, Julia McFarlane Diabetes Research Centre, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada

Costimulatory and coinhibitory signals are important for the maintenance of immune homeostasis both in the steady state and during immune responses. In this study, we explore the relative contributions of these signals to the rapid production of large amounts of cytokines by activated invariant NKT cells (iNKT cells). We find that upon antigenic stimulation, iNKT cells rapidly up-regulate programmed death (PD)-1 and induce high levels of PD ligand 1 and costimulatory molecules on the surface of cognate Ag-presenting dendritic cells and that iNKT cells require a CD28 signal to secrete cytokines in the presence of a PD-1/PD ligand 1 interaction. CD28-deficient iNKT cells synthesized but failed to secrete cytokines during activation, and blockade of the PD-1 pathway restored the ability of CD28-deficient iNKT cells to secrete cytokines. The opposing functions of CD28 and PD-1 thus tightly regulate the unique effector function iNKT cells.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the Canadian Diabetes Association (to Y.Y.) and the Canadian Institutes of Health Research (to Y.Y. and P.S.). The Julia McFarlane Diabetes Research Centre is supported by the Diabetes Association (Foothills). P.S. is a Scientist of the Alberta Heritage Foundation for Medical Research and a Juvenile Diabetes Research Foundation Scholar.

² J.W. and L.C. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Yang Yang, Department of Biochemistry and Molecular Biology, Julia MacFarlane Diabetes Research Centre, University of Calgary, 3330 Hospital Drive Northwest, Calgary, Alberta T2N 4N1, Canada. E-mail address: yyang{at}ucalgary.ca

⁴ Abbreviations used in this paper: iNKT cell, invariant NK T cell; DC, dendritic cell; GalCer, -galactosylceramide; PD, programmed death; PD-L, PD ligand; WT, wild type.