Responses against islet antigens in NOD mice are prevented by tolerance to proinsulin but not IGRP
Balasubramanian Krishnamurthy, … , Helen E. Thomas, Thomas W.H. Kay
Balasubramanian Krishnamurthy, … , Helen E. Thomas, Thomas W.H. Kay
Published December 1, 2006
Citation Information: J Clin Invest. 2006;116(12):3258-3265. https://doi.org/10.1172/JCI29602.
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Responses against islet antigens in NOD mice are prevented by tolerance to proinsulin but not IGRP

Abstract

Type 1 diabetes (T1D) is characterized by immune responses against several autoantigens expressed in pancreatic β cells. T cells specific for proinsulin and islet-specific glucose-6-phosphatase catalytic subunit–related protein (IGRP) can induce T1D in NOD mice. However, whether immune responses to multiple autoantigens are caused by spreading from one to another or whether they develop independently of each other is unknown. As cytotoxic T cells specific for IGRP were not detected in transgenic NOD mice tolerant to proinsulin, we determined that immune responses against proinsulin are necessary for IGRP-specific T cells to develop. On the other hand, transgenic overexpression of IGRP resulted in loss of intra-islet IGRP-specific T cells but did not protect NOD mice from insulitis or T1D, providing direct evidence that the response against IGRP is downstream of the response to proinsulin. Our results suggest that pathogenic proinsulin-specific immunity in NOD mice subsequently spreads to other antigens such as IGRP.

Authors

Balasubramanian Krishnamurthy, Nadine L. Dudek, Mark D. McKenzie, Anthony W. Purcell, Andrew G. Brooks, Shane Gellert, Peter G. Colman, Leonard C. Harrison, Andrew M. Lew, Helen E. Thomas, Thomas W.H. Kay

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Figure 1

IGRP206–214 tetramer–positive CD8+ T cell numbers in peripheral blood and spleens of NOD and NOD-PI mice.

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IGRP206–214 tetramer–positive CD8+ T cell numbers in peripheral blood an...
(A and B) Percentage of IGRP206–214-positive CD8+ T cells within (A) peripheral blood and (B) spleen. Data (mean ± SEM) are from mice 8 weeks (n = 8), 12 weeks (n = 12) and 15 weeks of age (n = 12). P < 0.005, NOD versus NOD-PI in peripheral blood at 12 weeks; P < 0.001, NOD versus NOD-PI in peripheral blood at 15 weeks; P < 0.02, NOD versus NOD-PI in spleen at 15 weeks. (C) Representative tetramer staining patterns. The numbers within dot plots indicate percentages of tetramer-positive CD8+ T cells.