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

Abstract

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

Autoreactive T cells in type 1 diabetes

“…The positive effects of treatment with an anti-memory cell agent in patients with recently diagnosed T1D supports the importance of memory autoreactive T cells in this disease (105,106). Memory autoreactive T cells were linked to T1D recurrence in transplanted patients, both in islet (107,108) and pancreas transplantation (109), despite immunosuppression.…”

Children diagnosed with both Type 1 diabetes and Celiac disease - An Immunological challenge

“…Previous observation of pancreatic grafts show that a large population of CD8 + pancreas-infiltrating lymphocytes lacks expression of CD28 [139] . Immune aberrancies have also been shown in the gut, in children who are prone to T1D, suggesting poor development of oral tolerance [125] .…”

T Cell Autoreactivity in the Transplant Milieu

“…A key observation in these studies is that some of the recurrent autoreactive T cells in post-SPK transplant patients shared similar or identical antigen-specific T cell receptor (TCR) with preexisting T cells in the same subject. TCR sequences were derived from tetramer-binding T cells at several time points, and identity of Vb sequences, including the complementary determining region 3 (CDR3) of the TCR (3,4,6), over time strongly suggests a persistent memory response generated by an autoreactive population expanded from a single progenitor.…”