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* Department of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom;
Nephrology and Transplant Directorate, University Hospital Of Wales, Cardiff, United Kingdom;
Academic Renal Unit, Southmead Hospital, Bristol, United Kingdom;
Centre de physiopathologie de Toulouse Purpan, Institut National de la Santé et de la Recherche Médicale, Unité 563/Universite Paul Savatier, Centre Hospitalier de l’Université Purpan, Toulouse, France;
¶ Section of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520; and
|| Section of Endocrinology, Yale University School of Medicine, New Haven, CT 06520
CD80 and CD86 both costimulate T cell activation. Their individual effects in vivo are difficult to study as they are coordinately up-regulated on APCs. We have studied mice expressing rat insulin promoter (RIP)-CD80 and RIP-CD86 on the NOD and NOD.scid genetic background to generate in vivo models, using diabetes as a readout for cytotoxic T cell activation. Accelerated spontaneous diabetes onset was observed in NOD-RIP-CD80 mice and the transfer of diabetes from 6-wk-old NOD mice to NOD.scid-RIP-CD80 mice was greater compared with NOD-RIP-CD86 and NOD.scid-RIP-CD86 mice, respectively. However, the secondary in vivo response was maintained if T cells were activated through CD86 costimulation compared with CD80. This was demonstrated by greater ability to cause recurrent diabetes in NOD-RIP-CD86 diabetic mice transplanted with 6-wk-old NOD islets and adoptively transferred diabetes from diabetic NOD-RIP-CD86 mice to NOD.scid mice. In vitro, CD80 costimulation enhanced cytotoxicity, proliferation, and cytokine secretion in activated CD8 T cells compared with CD86 costimulation. We demonstrated increased CTLA-4 and programmed death-1 inhibitory molecule expression following costimulation by both CD80 and CD86 (CD80 > CD86). Furthermore, T cells stimulated by CD80 were more susceptible to inhibition by CD4+CD25+ T cells. Overall, while CD86 does not stimulate an initial response as strongly as CD80, there is greater sustained activity that is seen even in the absence of continued costimulation. These functions have implications for the engineered use of costimulatory molecules in altering immune responses in a therapeutic setting.
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 I.J.T. was supported by a Wellcome Trust Prize Studentship, R.A.F. is an investigator of the Howard Hughes Medical Institute, and F.S.W. was a Wellcome Trust Senior Fellow in Clinical Science.
2 Address correspondence and reprint requests to Dr. F. Susan Wong, Department of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, U.K. E-mail address: susan.wong{at}bristol.ac.uk
3 Abbreviations used in this paper: PD-1, programmed death-1; RIP, rat insulin promoter.
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  F. S. Wong, L. Khai Siew, G. Scott, I. J. Thomas, S. Chapman, C. Viret, and L. Wen Activation of Insulin-Reactive CD8 T-Cells for Development of Autoimmune Diabetes Diabetes, May 1, 2009; 58(5): 1156 - 1164. [Abstract] [Full Text] [PDF]
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