Responses against islet antigens in NOD mice are prevented by tolerance to proinsulin but not IGRP
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
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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Research Article Metabolism

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 3

Reduced proliferation of CFSE-labeled IGRP206–214-specific CD8+ T cells in NOD-PI mice.

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Reduced proliferation of CFSE-labeled IGRP206–214-specific CD8+ T cells ...
CFSE-labeled CD8+ T cells isolated from NOD8.3 TCR transgenic mice were injected (4–6 × 106 cells/mouse) intravenously into NOD and NOD-PI mice of different ages. Cells were isolated from PLN and ILN 3 days later and analyzed for CFSE dilution by flow cytometry. (A) Percentage (mean ± SEM) of transferred cells dividing in NOD and NOD-PI mice (n = 4–10 mice per group at each time point). P < 0.004, NOD versus NOD-PI in PLN at 6 weeks; P < 0.0002, NOD versus NOD-PI in PLN at 8 weeks; P < 0.01, NOD versus NOD-PI in PLN at 12 weeks. (B) Representative histogram plot. The numbers within the histogram plots indicate percentages of CFSE-low cells.