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* King’s College London, Department of Immunobiology, London, United Kingdom;
Infectious Diseases and Microbiology Unit, Institute of Child Health, University College, London, United Kingdom;
King’s College London, Diabetes Research Group, London, United Kingdom; and
National Institute for Health Research Biomedical Research Centre at Guy’s and St. Thomas’ National Health Service Foundation Trust and King’s College, London, United Kingdom
Pancreatic islet endothelial cells (ECs) form the barrier across which autoreactive T cells transmigrate during the development of islet inflammation in type 1 diabetes. Little is known about the immune phenotype of islet ECs that might shape their molecular interaction with autoreactive T cells before and during the development of islet inflammation. In this study we examined the expression and functional significance of costimulatory molecules by human islet ECs. Freshly isolated human islet ECs constitutively expressed CD86 (B7-2) and ICOS ligand but not CD80 (B7-1) or CD40 costimulatory molecules. The functional activity of islet EC-expressed CD86 was examined by coculture of resting islet ECs with CD4 T cells stimulated by CD3 ligation alone. Marked T cell proliferation in the coculture was completely abrogated by mAb blockade of CD86, confirming that costimulatory properties are conferred on ECs by CD86 expression. In view of its location on the vasculature, we hypothesized a role for CD86 in T cell adhesion/transmigration. In keeping with this, adhesion/transmigration of activated (CD3 ligated) memory (CD45R0+) CD4 T cells across islet ECs was completely inhibited in the presence of CD86 blocking mAb. Identical results were obtained for T cell adhesion using either CTLA-4 blocking mAb or CTLA-4Ig (abatacept), indicating CTLA-4 as the T cell ligand for these CD86-mediated effects. These data suggest a novel role for CD86 expression on the microvasculature, whereby ligation of CTLA-4 on CD4 T cells by CD86 on islet ECs is key to the adhesion of recently activated T 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 Diabetes U.K. and the Juvenile Diabetes Research Foundation (postdoctoral fellowship 3-2007-643 to B.L.-O.). The authors acknowledge financial support from the Department of Health via the National Institute for Health Research comprehensive Biomedical Research Centre award to Guy’s and St Thomas’ National Health Service Foundation Trust in partnership with King’s College London.
2 Address correspondence and reprint requests to Prof. Mark Peakman, Department of Immunobiology, King’s College London, Second Floor Borough Wing, Guy’s Hospital, Great Maze Pond, London SE1 9RT, U.K. E-mail address: mark.peakman{at}kcl.ac.uk.
3 Abbreviations used in this paper: T1D, type 1 diabetes; EC, endothelial cell; ICOS-L, ICOS ligand; MEC, microvascular endothelial cell.
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