Epitope specificity, cytokine production profile and diabetogenic activity of insulin‐specific T cell clones isolated from NOD mice

Abstract

T cells are known to play an important role in beta cell destruction in the nonobese diabetic (NOD) mouse model of Type I diabetes and islet-specific T cell clones have been demonstrated to be capable of adoptive transfer of diabetes. One important issue involves the identity of beta cell antigens that are recognized by nominally islet cell-specific T cell clones. We have previously reported that insulin-specific T cells are a predominant component of islet-specific T cells isolated from islet infiltrates of pre-diabetic NOD mice. In this report we examine six independently derived insulin-specific T cell clones established from islet infiltrates of pre-diabetic NOD mice in detail. All six clones were found to be specific to a region of the insulin molecule defined by a synthetic peptide encompassing residues 9-23 of the B chain. Despite this restricted specificity, each member of this panel exhibited a distinct receptor specificity defined either by V beta usage or antigen fine specificity. Five clones produced interferon (IFN)-gamma but not interleukin (IL)-4, placing them in the T helper type 1 (TH1)-like category whereas one clone produced both IL-4 and IFN-gamma, a characteristic of TH0 cells. All six clones were capable of either acceleration of diabetes in young NOD mice or adoptive transfer to NODscid mice. Taken together, these results suggest that spontaneously arising insulin-specific T cells participate in beta cell destruction during development of diabetes in NOD mice.

Mesenchymal stem cells protect NOD mice from diabetes by inducing regulatory T cells

“…Animals were immunised subcutaneously with 100 µg insulin B9-23 peptide (amino acids 9-23 of the B chain; SHLVEALYLVCGERG) [17,18] in complete Freund's adjuvant, together with 140 µg of a helper peptide consisting of amino acids 128-140 of hepatitis B virus core antigen (TPPAYRPPNAPIL), at the base of the tail. After 12-14 days, an i.p.…”

The role of T-cells in the pathogenesis of Type 1 diabetes: From cause to cure

“…It is clear that in NOD mice the disease process is Th-1 driven. However, although Th-2 cells dominate non-destructive periinsulitis in these mice, IL-4 producing Th-cell clones are capable of adoptive transfer of insulitis or even diabetes to non-diabetic immunoincompetent NODscid recipients [89,90], and incapable to prevent disease [89].…”

Do the peptide-binding properties of diabetogenic class II molecules explain autoreactivity?

“…Insulin, and particularly the 9-23 peptide of the insulin beta chain, is a primary target of T cell reactivity in both the human disease and the NOD mouse [38,39] (in this issue, contribution by Eisenbarth). Initial binding studies of the B:(9-23) peptide to soluble I-A g7 in detergent free conditions revealed poor binding and fast dissociation rates [10,13,14,40].…”