Processing and Presentation of the Islet Autoantigen GAD by Vascular Endothelial Cells Promotes Transmigration of Autoreactive T-Cells

Greening, James; Tree, Timothy; Kotowicz, Karolena T.; Halteren, Astrid G. van; Roep, Bart O.; Klein, Nigel; Peakman, Mark

doi:10.2337/diabetes.52.3.717

Cited by 67 publications

(60 citation statements)

References 42 publications

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“…Subsequent CD4 + T cell-APC interaction results in acquisition of a regulatory phenotype by the CD4 + T cell [23]. CD8 + CD28 − T cells have been shown to interact with human endothelial cells [24], which may act as 'target' APCs in solid organ transplantation as well as islet autoimmunity [25]. Concordantly, ILT-3 (also known as LILRB4) precursor RNA was expressed and retained in nuclei of resting endothelial cells [16].…”

Section: Discussionmentioning

confidence: 93%

Accumulation of autoreactive effector T cells and allo-specific regulatory T cells in the pancreas allograft of a type 1 diabetic recipient

et al. 2008

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Aims/hypothesis Simultaneous kidney-pancreas transplantation is an established treatment for patients with type 1 diabetes and end-stage renal failure, even though restored beta cell function may become affected by recurrent islet autoimmunity or graft rejection. We characterised infiltrating lymphocytes isolated from a pancreatic graft with normal endocrine function in a kidney-pancreas recipient with type 1 diabetes. Methods The pancreas graft was removed due to recurrent graft pancreatitis of unknown cause. Pancreas-infiltrating lymphocytes and peripheral blood mononuclear cells (PBMC) were isolated and characterised phenotypically and functionally.Results Compared with PBMC, pancreas-infiltrating lymphocytes exhibited a distinct activation/memory phenotype and T cell receptor profile that were indicative of selective infiltration of the pancreas. Islet autoreactive CD8 + T cells could be detected in the pancreas and were increased in frequency compared with PBMC. Additionally, an augmentation of CD8 + CD28 − regulatory T cells was observed in the pancreas; these induced expression of the inhibitory receptor immunoglobulin-like transcript-3 on antigen-presenting cells in a donor HLA class I-specific manner. Conclusions/interpretation These data demonstrate the simultaneous presence of regulatory and effector T cells in the pancreas allograft of a recipient with type 1 diabetes. They also indicate that circulating islet autoreactive T cells may reflect immunological processes in pancreatic tissue, even though their frequency in the periphery may lead to underestimation of their presence in the pancreas. Additional specificities were also present in the pancreas that were undetectable in the circulation.Keywords Effector T cells . Pancreas transplantation . Regulatory T cells . Type 1 diabetesAbbreviations APC antigen presenting cell CCR7 chemokine (C-C motif) receptor 7 CDR3 complementarity-determining region 3 IMDM Iscove's Modified Dulbecco's Medium IGRP islet-specific glucose-6-phosphatase catalytic subunit-related protein ILT immunoglobulin-like transcript mAbs monoclonal antibodies MACS magnetic-activated cell-sorting Diabetologia (2009) 52:494-503

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Section: Discussionmentioning

confidence: 93%

Accumulation of autoreactive effector T cells and allo-specific regulatory T cells in the pancreas allograft of a type 1 diabetic recipient

et al. 2008

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“…Like hsp60-specific T cells, GAD65-specific T cells could only be traced in the pancreas when co-injected with 38-kDa-specific T cells. This poor accumulation could be explained by the fact that the GAD65-specific T cell clone requires autoantigenpresentation by HLA-DR3 + endothelial cells for optimal migration across human vascular endothelium [46]. Unstimulated T cells do not transmigrate, suggesting that only appropriately stimulated autoreactive T cells reach the endocrine islet mass.…”

Section: Discussionmentioning

confidence: 99%

Homing of human autoreactive T cells into pancreatic tissue of NOD-scid mice

Halteren¹,

Kardol²,

Mulder³

et al. 2004

Diabetologia

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Aims/hypothesis: An important prerequisite for the initiation of pancreatic islet inflammation is the recruitment of pathogenic T cells. We investigated the in vivo migration patterns of human islet-reactive T cell clones after transfer into compromised hosts. Methods: NOD-scid mice were injected with a mixture of human autoreactive T cells and antigen-presenting cells. Survival and migration of T cells was analysed by fluorescenceactivated cell sorter and immunohistochemical analysis of various tissues.

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“…We also characterised the immunological profile of these islet MECs, since it is well established that endothelial cells have a role in inflammatory processes, being able to secrete numerous cytokines and chemokines, and participate in presentation of antigens to T cells [25,[40][41][42]. Indeed, during insulitis in type 1 diabetes, endothelial cells surrounding the islets have been shown to assume an activated phenotype [20][21][22][23][24].…”

Section: Discussionmentioning

confidence: 99%

Primary and immortalised human pancreatic islet endothelial cells: phenotypic and immunological characterisation

et al. 2005

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Aims/hypothesis: Studies on the biology of the microvascular endothelial cells (MECs) that surround and penetrate the pancreatic islets are hampered by difficulties in isolating and culturing large numbers of pure cells. We aimed to morphologically and functionally characterise primary MECs purified and cultured from human islets, and to establish a simian virus 40 (SV40)-immortalised cell line from these primary cultures. Materials and methods: Human islet MECs were extracted and purified using anti-CD105 coated immunomagnetic beads, and endothelial markers and surface molecules analysed by flow cytometric analysis. An immortalised cell line was then established by using a chimeric adeno5/SV40 virus. Results: Islet MECs expressed classic and specific endothelial markers, a high basal level of intercellular adhesion molecule-1, and low levels of E-selectin and TNF (previously known as TNF-α) inducible vascular cell adhesion molecule-1. IFNG (previously known as IFN-γ) induced expression of HLA class II molecules. The immortalised islet MECs expanded rapidly, exhibited increased DNA synthesis, and were passaged approximately 30 times, without signs of senescence. They retained the endothelial characteristics of the parental cells, and behaved as the primary cells in terms of TNF stimulation of expression of adhesion molecules and support of leucocyte adhesion and transmigration. Conclusions/interpretation: The immortalised islet MECs that we have established could effectively represent a substitute for primary counterparts for in vitro studies on the role of the microvasculature in pathophysiological processes involved in type 1 and type 2 diabetes.

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Processing and Presentation of the Islet Autoantigen GAD by Vascular Endothelial Cells Promotes Transmigration of Autoreactive T-Cells

Cited by 67 publications

References 42 publications

Accumulation of autoreactive effector T cells and allo-specific regulatory T cells in the pancreas allograft of a type 1 diabetic recipient

Accumulation of autoreactive effector T cells and allo-specific regulatory T cells in the pancreas allograft of a type 1 diabetic recipient

Homing of human autoreactive T cells into pancreatic tissue of NOD-scid mice

Primary and immortalised human pancreatic islet endothelial cells: phenotypic and immunological characterisation

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