β Cell-Specific CD4+ T Cell Clonotypes in Peripheral Blood and the Pancreatic Islets Are Distinct

Abstract

Type 1 diabetes is an autoimmune disease mediated by β cell-specific CD4+ and CD8+ T cells. Tracking β cell-specific T cells is one approach to monitor the diabetogenic response in at risk or diabetic individuals. Such analyses, however, are limited to PBL because T cells infiltrating the pancreatic islets are normally inaccessible. A key issue is whether peripheral β cell-specific T cells accurately reflect those cells infiltrating the target tissue. We investigated the properties of CD4+ T cells specific for a mimetic epitope recognized by the BDC2.5 clonotypic TCR in NOD mice. Soluble IAg7-Ig (sIAg7-Ig) multimer complexes covalently linked to a mimetic BDC peptide (sIAg7-mBDC) were used to identify or isolate CD4+ T cells from PBL and the islets of NOD mice. A temporal increase in sIAg7-mBDC binding (g7-mBDC+) T cells corresponding with the progression of β cell autoimmunity was detected in both PBL and islets in NOD female mice. In contrast to T cells in PBL, however, the majority of islet g7-mBDC+ T cells exhibited a type 1 phenotype, and mediated diabetes upon transfer into NOD.scid recipients. TCR-β and CDR-β gene usage of single islet-infiltrating g7-mBDC+ CD4+ T cells from individual NOD mice showed a restricted repertoire dominated by one or two clones typically expressing TCR β-chain variable TRBV-15. In contrast, a distinct and diverse TCR repertoire was detected for PBL-derived g7-mBDC+ T cells. These results demonstrate that PBL and islet CD4+ T cells specific for a given β cell epitope can differ regarding pathogenicity and TCR repertoire.

Tissue distribution and clonal diversity of the T and B cell repertoire in type 1 diabetes

“…It is widely accepted that diabetogenic T cells are enriched within the pancreatic islets and pLN in NOD mice (8,31). This notion emanates from animal model studies, such as those by Lennon et al, which demonstrated that islet entry and accumulation is an antigen-specific, cell-autonomous event (7).…”

Global gene expression changes in type 1 diabetes: Insights into autoimmune response in the target organ and in the periphery

“…In addition it seems that peripheral diabetogenic CD4+ T cell clonotypes have different phenotype TCR repertoire and pathogenicity than islet-infiltrating clonotypes [26]. However, immunological alterations in the periphery exist and can have important prognostic, diagnostic and follow-up implications for identifying prediabetic individuals or recurrent autoimmunity after islets or pancreas transplantation.…”

TCR Bias of In Vivo Expanded T Cells in Pancreatic Islets and Spleen at the Onset in Human Type 1 Diabetes

“…One such study reported the repertoire of T cells from the PLN of diabetic donors expanded in vitro with insulin, but none of the clones could be found in the spleen of the same donor (21). Ex vivo experiments published by Li et al (40) using the NOD model revealed that the TCR of intrapancreatic T cells that were sorted against the mimotope of the diabetogenic clone BDC2.5 were not found in peripheral blood or were present at a very low frequency. In a different study in NOD mice, Sarukhan et al (41) could not find any of the most abundant islet-specific T cell clones in the spleen.…”