Different diabetogenic potential of autoaggressive CD8+ clones associated with IFN-gamma-inducible protein 10 (CXC chemokine ligand 10) production but not cytokine expression, cytolytic activity, or homing characteristics.
Type 1 diabetes mellitus is an autoimmune disease characterized by T cell-mediated destruction of the insulin-producing beta 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 beta 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 GAD65(515-524) or insulin B-chain(15-23) peptides. Although these two clones were identical in most phenotypic and functional aspects, for example cytokine production and killing of autologous beta cells, they differed in the expression of IFN-gamma-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-chain(15-23)-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-gamma-inducible protein-10 by autoaggressive CD8(+) lymphocytes might determine their diabetogenic capacity by affecting recruitment of cells to the insulitic lesion.
Ejrnaes
Mette
M
Department of Developmental Immunology, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121, USA.
Videbaek
Nicoline
N
Christen
Urs
U
Cooke
Anne
A
Michelsen
Birgitte K
BK
von Herrath
Matthias
M
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000276:immunology*; D002478:Cells, Cultured; D054357:Chemokine CXCL10; D018925:Chemokines / Q000096:biosynthesis / Q000378:metabolism; D019743:Chemokines, CXC / Q000096:biosynthesis* / Q000378:metabolism; D002999:Clone Cells; D016207:Cytokines / Q000096:biosynthesis* / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D005968:Glutamate Decarboxylase / Q000008:administration & dosage / Q000276:immunology; D007274:Injections, Intraperitoneal; D007328:Insulin / Q000008:administration & dosage / Q000276:immunology; D007515:Islets of Langerhans / Q000276:immunology / Q000473:pathology*; D016381:Islets of Langerhans Transplantation / Q000276:immunology; D007527:Isoenzymes / Q000008:administration & dosage / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology
D054357:Chemokine CXCL10; D018925:Chemokines; D019743:Chemokines, CXC; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D007328:Insulin; D007527:Isoenzymes; D010446:Peptide Fragments; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2