Major histocompatibility complex class I-restricted T cells are required for all but the end stages of diabetes development in nonobese diabetic mice and use a prevalent T cell receptor α chain gene rearrangement

Abstract

Nonobese diabetic (NOD) mice develop insulin-dependent diabetes mellitus due to autoimmune T lymphocyte-mediated destruction of pancreatic ␤ cells. Although both major histocompatibility complex class I-restricted CD8؉ and class II-restricted CD4 ؉ T cell subsets are required, the specific role each subset plays in the pathogenic process is still unclear. Here we show that class I-dependent T cells are required for all but the terminal stages of autoimmune diabetes development. To characterize the diabetogenic CD8؉ T cells responsible, we isolated and propagated in vitro CD8 ؉ T cells from the earliest insulitic lesions of NOD mice. They were cytotoxic to NOD islet cells, restricted to H-2K d , and showed a diverse T cell receptor ␤ chain repertoire. In contrast, their ␣ chain repertoire was more restricted, with a recurrent amino acid sequence motif in the complementarity-determining region 3 loop and a prevalence of V␣17 family members frequently joined to the J␣42 gene segment. These results suggest that a number of the CD8 ؉ T cells participating in the initial phase of autoimmune ␤ cell destruction recognize a common structural component of K d ͞peptide complexes on pancreatic ␤ cells, possibly a single peptide.Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease characterized by T cell-mediated destruction of pancreatic islet ␤ cells (1). The nonobese diabetic (NOD) mouse (2) constitutes a widely studied model system for IDDM, as it shares many of the characteristics of the human disease. For example, human patients and NOD mice both develop lymphocytic infiltration of islets (insulitis) and subsequent ␤ cell destruction mediated by T lymphocytes. Cell-surface ␣␤ T cell receptors (TCRs) enable such T lymphocytes to recognize specific antigens on the surfaces of target cells in the form of peptides complexed with major histocompatibility complex (MHC) molecules, with CD8 ϩ cytotoxic T lymphocytes being restricted to class I MHC molecules and CD4 ϩ T cells to class II.Certain unusual MHC class II alleles provide the strongest genetic component of IDDM susceptibility in both humans and NOD mice (3). Thus, it is not surprising that autoreactive CD4 haplotype (15). However, although the requirement for CD8 ϩ T cells in IDDM development is clear, whether they are only needed to initiate the earliest events of ␤ cell destruction or are critical to all stages of diabetogenesis remained unknown and is one of the questions addressed in this study.It is also necessary to define the characteristics and specificities of MHC class I-restricted effectors participating in the earliest initiative phases of IDDM. In view of the importance of understanding the nature of these initiating T cells, we have developed a technique for the isolation of monoclonal and oligoclonal populations of NOD ␤ cell-cytotoxic CD8 ϩ T cells that uses islets from a newly developed stock of NODscid.RIPB7 mice as a potent source of stimulating antigen. This approach has enabled us to isolate cytotoxic CD8 ϩ T cells from pred...

Systemic Administration of Agonist Peptide Blocks the Progression of Spontaneous CD8-Mediated Autoimmune Diabetes in Transgenic Mice Without Bystander Damage

“…However, this approach has to be validated in a nontransgenic model of organ-specific autoimmune disease. In that respect, this approach might prove to be effective in NOD mice, in which autoreactive CD8 ϩ T cells participate in disease progression and in which a homogeneous autoreactive CD8 ϩ T cell population has been identified (19,(65)(66)(67). For human autoimmune diseases, where peptide therapy is at an early stage of clinical development, a combination of class I-and class II-binding self-peptides should be considered, to target both autoreactive CD8 ϩ and CD4 ϩ T cells.…”

Autoreactive CD8 T cells associated with β cell destruction in type 1 diabetes

“…Several studies have shown that prevention of diabetes can be achieved in animal models by the down-regulation of autoreactive T cells after administration of immunodominant peptides derived from the major ␤ cell antigens. Prevention of diabetes in animal models has been achieved through oral, intranasal, i.v., or s.c. administration of B9 peptide from the insulin B chain (39), peptide B24-C36 from proinsulin (7,40), peptides from glutamic acid decarboxylase 65 (41)(42)(43), or peptides from the heat-shock protein hsp60 (44,45). However, the short half-life of peptides in the circulation and the need for repeated administrations are some of the limitations of peptide therapy.…”

“…This phenomenon was first demonstrated by the finding that MHC class I-deficient NOD mice were completely type 1 diabetes-resistant (4,5). Subsequent analyses indicated that MHC class I-dependent T cell responses are an essential component of both the initiation and progression of pancreatic ␤ cell destruction, ultimately leading to type 1 diabetes development in NOD mice (6,7).…”

Metalloprotease-Mediated Shedding of Enzymatically Active Mouse ecto-ADP-ribosyltransferase ART2.2 Upon T Cell Activation

“…Splenic T cells from these donors were activated in vitro by coculture with collagenase-isolated islets from NODLtSz.scid.RIPB7 mice expressing the costimulatory B7-1 membrane protein under control of the insulin promoter were also provided by Dr. Serreze and are described elsewhere (20).…”