Early Th1 response in unprimed nonobese diabetic mice to the tyrosine phosphatase-like insulinoma-associated protein 2, an autoantigen in type 1 diabetes.
The insulinoma-associated protein 2 (IA-2) is a phosphatase-like autoantigen inducing T and B cell responses associated with human insulin-dependent diabetes mellitus (IDDM). We now report that T cell responses to IA-2 can also be detected in the nonobese diabetic (NOD) mouse, a model of human IDDM. Cytokine secretion in response to purified mouse rIA-2, characterized by high IFN-gamma and relatively low IL-10 and IL-6 secretion, was elicited in spleen cells from unprimed NOD mice. Conversely, no response to IA-2 was induced in spleen cells from BALB/c, C57BL/6, or Biozzi AB/H mice that express, like NOD, the I-A(g7) class II molecule, but are not susceptible to spontaneous IDDM. The IA-2-induced IFN-gamma response in NOD spleen cells could already be detected at 3 wk and peaked at 8 wk of age, whereas the IL-10 secretion was maximal at 4 wk of age and then waned. IA-2-dependent IFN-gamma secretion was induced in CD4(+) cells from spleen as well as pancreatic and mesenteric lymph nodes. It required Ag presentation by I-A(g7) molecules and engagement of the CD4 coreceptor. Interestingly, cytokines were produced in the absence of cell proliferation and IL-2 secretion. The biological relevance of the response to IA-2 is indicated by the enhanced IDDM following a single injection of the recombinant protein emulsified in IFA into 18-day-old NOD mice. In addition, IFN-gamma production in response to IA-2 and IDDM acceleration could be induced by IL-12 administration to 12-day-old NOD mice. These results identify IA-2 as an early T cell-inducing autoantigen in the NOD mouse and indicate a role for the IA-2-induced Th1 cell response in IDDM pathogenesis.
Trembleau
S
S
Roche Milano Ricerche, Milan, Italy.
Penna
G
G
Gregori
S
S
Magistrelli
G
G
Isacchi
A
A
Adorini
L
L
D000375:Aging / Q000276:immunology; D000818:Animals; D017951:Antigen Presentation; D001324:Autoantigens / Q000008:administration & dosage / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology / Q000276:immunology*; D004334:Drug Administration Schedule; D000939:Epitopes / Q000276:immunology; D005260:Female; D005968:Glutamate Decarboxylase / Q000008:administration & dosage / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology / Q000378:metabolism; D007114:Immunization; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000008:administration & dosage; D007515:Islets of Langerhans / Q000276:immunology; D007527:Isoenzymes / Q000008:administration & dosage / Q000276:immunology; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism*
D001324:Autoantigens; D016207:Cytokines; D000939:Epitopes; D000949:Histocompatibility Antigens Class II; C407099:I-A g7 antigen; D007527:Isoenzymes; D008565:Membrane Proteins; D011994:Recombinant Proteins; D018664:Interleukin-12; D007371:Interferon-gamma; C516862:PTPRN protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; C516863:Ptprn protein, mouse; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2