Different Diabetogenic Potential of Autoaggressive CD8+ Clones Associated with IFN-γ-Inducible Protein 10 (CXC Chemokine Ligand 10) Production but Not Cytokine Expression, Cytolytic Activity, or Homing Characteristics

Abstract

Type 1 diabetes mellitus is an autoimmune disease characterized by T cell-mediated destruction of the insulin-producing β cells in the islets of Langerhans. From studies in animal models, CD8+ T cells recognizing autoantigens such as islet-specific glucose-6-phosphatase catalytic subunit-related protein, insulin, or glutamic acid decarboxylase (GAD) are believed to play important roles in both the early and late phases of β cell destruction. In this study, we investigated the factors governing the diabetogenic potential of autoreactive CD8+ clones isolated from spleens of NOD mice that had been immunized with GAD65515–524 or insulin B-chain15–23 peptides. Although these two clones were identical in most phenotypic and functional aspects, for example cytokine production and killing of autologous β cells, they differed in the expression of IFN-γ-inducible protein-10, which was only produced at high levels by the insulin-specific clone, but not by the GAD65-specific clone, and other autoantigen-specific nonpathogenic CD8 T cell clones. Interestingly, upon i.p. injection into neonatal mice, only the insulin B-chain15–23-reactive CD8+ T clone accelerated diabetes in all recipients after 4 wk, although both insulin- and GAD-reactive clones homed to pancreas and pancreatic lymph nodes with similar kinetics. Diabetes was associated with increased pancreatic T cell infiltration and, in particular, recruitment of macrophages. Thus, secretion of IFN-γ-inducible protein-10 by autoaggressive CD8+ lymphocytes might determine their diabetogenic capacity by affecting recruitment of cells to the insulitic lesion.

Salmonella typhimurium Infection in Nonobese Diabetic Mice Generates Immunomodulatory Dendritic Cells Able to Prevent Type 1 Diabetes

“…Expression of CXCL10 within the pancreas has been linked to the recruitment of lymphocytes into the pancreas by a diabetogenic CD8 T cell clone, while expression within the PLN appears to retain autoreactive T cells and prevent pancreatic infiltration (30,33). Raised CXCL10 levels have been demonstrated after infection of mice with a number of pancreas-tropic viruses capable of triggering T1D in a mouse model, while neutralization of CXCL10 prevented T1D in this model (34).…”

“…The expression pattern of chemokines has been shown to control autoreactive T cell migration in the initiation and prevention of T1D (28,30,33). Prevention of T1D in NOD mice exposed to the NKT cell ligand ␣-galactosylceramide has been linked to alterations in chemokine expression patterns and the preferential retention of transferred autoreactive CD8 ϩ T cells in the PLN (44).…”

IL-23 Drives Pathogenic IL-17-Producing CD8+ T Cells

“…In contrast, Ejrnaes et al found that the diabetogenic potential of Tc1 clones is associated with IP-10 (CXCL10) production but not with cytokine expression, cytolytic activity, or homing characteristics. The IP-10-expressing Tc1 clone led to destructive insulitis characterized by the presence of more T cells and particularly macrophages, suggesting that CD8 ϩ T cells can induce diabetes by recruiting other immune cell types to the site of inflammation (48). We found similar low levels of IP-10 in OT-I cultures treated with TGF-␤1 plus IL-6 or IL-23, suggesting that IP-10 does not play a role in diabetogenicity of these cells (supplemental Fig.…”

Minimal Impact of a De Novo–Expressed β-Cell Autoantigen on Spontaneous Diabetes Development in NOD Mice

“…Generation of NP396-and GP33-specific NOD T-cell clones. The generation and maintenance of LCMV-specific T-cell clones in long-term cultures have been previously described (25,26). In brief, the NP396-specific NOD T-cell clone 9-A-8 and the GP33-specific NOD T-cell clone 13-G-8 were isolated from LCMV-infected NOD recipients and stimulated frequently with irradiated NP396 or GP33 peptide-loaded syngeneic macrophages, respectively, and recombinant human IL-2 (20 units/ml).…”