Autoimmunity to both proinsulin and IGRP is required for diabetes in nonobese diabetic 8.3 TCR transgenic mice.
T cells specific for proinsulin and islet-specific glucose-6-phosphatase catalytic subunit related protein (IGRP) induce diabetes in nonobese diabetic (NOD) mice. TCR transgenic mice with CD8(+) T cells specific for IGRP(206-214) (NOD8.3 mice) develop accelerated diabetes that requires CD4(+) T cell help. We previously showed that immune responses against proinsulin are necessary for IGRP(206-214)-specific CD8(+) T cells to expand. In this study, we show that diabetes development is dramatically reduced in NOD8.3 mice crossed to NOD mice tolerant to proinsulin (NOD-PI mice). This indicates that immunity to proinsulin is even required in the great majority of NOD8.3 mice that have a pre-existing repertoire of IGRP(206-214)-specific cells. However, protection from diabetes could be overcome by inducing islet inflammation either by a single dose of streptozotocin or anti-CD40 agonist Ab treatment. This suggests that islet inflammation can substitute for proinsulin-specific CD4(+) T cell help to activate IGRP(206-214)-specific T cells.
Krishnamurthy
Balasubramanian
B
St Vincent's Institute, Fitzroy, VIC, Australia.
Mariana
Lina
L
Gellert
Shane A
SA
Colman
Peter G
PG
Harrison
Leonard C
LC
Lew
Andrew M
AM
Santamaria
Pere
P
Thomas
Helen E
HE
Kay
Thomas W H
TW
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D015551:Autoimmunity / Q000187:drug effects / Q000276:immunology*; D002478:Cells, Cultured; D003920:Diabetes Mellitus / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000517:prevention & control; D005952:Glucose-6-Phosphatase / Q000378:metabolism / Q000494:pharmacology*; D007108:Immune Tolerance / Q000276:immunology; D007515:Islets of Langerhans / Q000201:enzymology*; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D011384:Proinsulin / Q000494:pharmacology*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism*
D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D011384:Proinsulin; D005952:Glucose-6-Phosphatase