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Deaf1 isoforms control the expression of genes encoding peripheral tissue antigens in the pancreatic lymph nodes during type 1 diabetes

Nature Immunology volume 10, pages 1026–1033 (2009)Cite this article

Abstract

Type 1 diabetes may result from a breakdown in peripheral tolerance that is partially controlled by the expression of peripheral tissue antigens (PTAs) in lymph nodes. Here we show that the transcriptional regulator Deaf1 controls the expression of genes encoding PTAs in the pancreatic lymph nodes (PLNs). The expression of canonical Deaf1 was lower, whereas that of an alternatively spliced variant was higher, during the onset of destructive insulitis in the PLNs of nonobese diabetic (NOD) mice. We identified an equivalent variant Deaf1 isoform in the PLNs of patients with type 1 diabetes. Both the NOD mouse and human Deaf1 variant isoforms suppressed PTA expression by inhibiting the transcriptional activity of canonical Deaf1. Lower PTA expression resulting from the alternative splicing of DEAF1 may contribute to the pathogenesis of type 1 diabetes.

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Figure 1: Expression of PTAs and Deaf1 isoforms in the PLNs of NOD mice.
Figure 2: Quantification of the expression of DF1 and DF1-VAR1 in NOD PLNs.
Figure 3: Cellular localization, formation of heterodimers and transcriptional activity of DF1 and DF1-VAR1.
Figure 4: Analysis of Deaf1-deficient mice.
Figure 5: Deaf1 regulates gene expression in NIH3T3 cells.
Figure 6: Regulation of PTA expression in NOD PLNs and LN CD45− cells by DF1 and DF1-VAR1.
Figure 7: Identification and characterization of an alternatively spliced Deaf1 isoform in human PLNs.

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GenBank/EMBL/DDBJ

Gene Expression Omnibus

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Acknowledgements

We thank H. Iwai and C. Taylor for technical assistance; J. Visvader (The Walter and Eliza Hall Institute of Medical Research) for Deaf1-deficient mice; and the Network for Pancreatic Organ Donors with Diabetes (Juvenile Diabetes Research Foundation) and the National Disease Research Interchange for human PLNs and spleen samples. Supported by the US National Institutes of Health (U01 DK078123-03, U19-DK 61934 and U19-AI050864 to C.G.F.), the Canadian Institutes of Health Research (P.R.A. and M.C.) and the American Diabetes Association (L.Y.).

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Authors and Affiliations

  1. Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, California, USA

    Linda Yip, Leon Su, Deqiao Sheng, Pearl Chang, C Garrison Fathman & Rémi J Creusot

  2. Department of Pathology, University of Florida, Gainesville, Florida, USA

    Mark Atkinson

  3. Ottawa Health Research Institute (Neuroscience) and Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada

    Margaret Czesak & Paul R Albert

  4. Department of Cancer Immunology and AIDS, Dana Farber Cancer Institute, Boston, Massachusetts, USA

    Ai-Ris Collier & Shannon J Turley

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  1. Linda Yip
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Contributions

L.Y. did microarray and quantitative PCR assays, cloned full-length DF1-VAR1 and Hu-DF1-VAR, synthesized DF1-VAR1, Hu-DF1 and Hu-DF1-VAR, did subcellular localization and siRNA experiments, assessed Deaf1-deficient mice for lymphocyte infiltration and serum autoantibodies, prepared the manuscript and composed the figures; R.J.C. extracted tissues for microarray and quantitative PCR, isolated cellular subsets from PLNs and, with P.C., isolated and immortalized the CD45− cells; D.S. cloned the DF1 isoform and synthesized DF1 fusion proteins; M.A. (and the Network for Pancreatic Organ Donors with Diabetes) provided human PLNs and spleen samples; M.C. and P.R.A. provided the Deaf1-deficient mice and provided guidance on work with these mice; A.-R.C. and S.J.T. provided expertise and guidance on the isolation of the CD45− lymph node stromal elements; L.S. did the immunoblot, coimmunoprecipitation and luciferase reporter assays and, with C.G.F., R.J.C. and L.Y., was involved in all aspects of the planning and direction of this work; all authors reviewed and edited the manuscript; and C.G.F. provided most of the funding.

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Correspondence to C Garrison Fathman.

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Yip, L., Su, L., Sheng, D. et al. Deaf1 isoforms control the expression of genes encoding peripheral tissue antigens in the pancreatic lymph nodes during type 1 diabetes. Nat Immunol 10, 1026–1033 (2009). https://doi.org/10.1038/ni.1773

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