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A defect in central tolerance in NOD mice

Nature Immunology volume 2, pages 1025–1031 (2001)Cite this article

Abstract

The predisposition of nonobese diabetic (NOD) mice to develop autoimmune disease is usually attributed to defects in peripheral tolerance mechanisms. Here, evidence is presented that NOD mice display a defect in central tolerance (negative selection) of thymocytes. Impaired central tolerance in NOD mice was most prominent in a population of semi-mature thymocytes found in the medulla. The defect was apparent in vivo as well as in vitro, was independent of IAβg7 expression and affected both Fas-dependent and Fas-independent pathways of apoptosis; for Fas-dependent apoptosis, the defective tolerance of NOD thymocytes correlated with the strong T cell receptor–mediated up-regulation of caspase 8–homologous FLICE (Fas-associated death-domain-like interleukin 1β–converting enzyme)-inhibitory protein. In light of these findings, disease onset in NOD mice may reflect defects in central as well as peripheral tolerance.

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Figure 1: Susceptibility of immature and semi-mature thymocytes to in vitro tolerance induction.
Figure 2: Role of costimulation and cytokines in negative selection.
Figure 3: Negative selection of NOD HSAhiCD4+CD8− thymocytes in vivo.
Figure 4: SEB-induced negative selection of NOD HSAhiCD4+CD8− thymocytes in vivo.
Figure 5: Expression of activation markers after exposing thymocytes to graded concentrations of TCR mAb plus a fixed concentration of CD28 mAbs.
Figure 6: Sensitivity of thymocytes to Fas-dependent apoptosis and the role of cFLIP.

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Acknowledgements

We thank B. Marchand for typing the manuscript and R. Salmon for assistance in developing the RT-PCR system for the FLIP gene. Supported by grants CA38355, AI21487, AI46710 and AG01743 from the United States Public Health Service.

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  1. Department of Immunology, IMM4, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, 92037, CA, USA

    Hidehiro Kishimoto & Jonathan Sprent

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Correspondence to Jonathan Sprent.

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Kishimoto, H., Sprent, J. A defect in central tolerance in NOD mice. Nat Immunol 2, 1025–1031 (2001). https://doi.org/10.1038/ni726

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