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Temporal induction of immunoregulatory processes coincides with age-dependent resistance to viral-induced type 1 diabetes

Genes & Immunity volume 14, pages 387–400 (2013)Cite this article

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Abstract

The dilute plasma cytokine milieu associated with type 1 diabetes (T1D), while difficult to measure directly, is sufficient to drive transcription in a bioassay that uses healthy leukocytes as reporters. Previously, we reported disease-associated, partially IL-1 dependent, transcriptional signatures in both T1D patients and the BioBreeding (BB) rat model. Here, we examine temporal signatures in congenic BBDR.lyp/lyp rats that develop spontaneous T1D, and BBDR rats where T1D progresses only after immunological perturbation in young animals. After weaning, the BBDR temporal signature showed early coincident induction of transcription related to innate inflammation as well as IL-10- and TGF-β-mediated regulation. BBDR plasma cytokine levels mirrored the signatures showing early inflammation, followed by induction of a regulated state that correlated with failure of virus to induce T1D in older rats. In contrast, the BBDR.lyp/lyp temporal signature exhibited asynchronous dynamics, with delayed induction of inflammatory transcription and later, weaker induction of regulatory transcription, consistent with their deficiency in regulatory T cells. Through longitudinal analyses of plasma-induced signatures in BB rats and a human T1D progressor, we have identified changes in immunoregulatory processes that attenuate a preexisting innate inflammatory state in BBDR rats, suggesting a mechanism underlying the decline in T1D susceptibility with age.

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Acknowledgements

The authors thank the patient who participated in this study as well as the physicians, nurses and staff of Children’s Hospital of Wisconsin and The Max McGee National Research Center for Juvenile Diabetes who assisted in subject recruitment and sample collection/processing. This work was supported by the Juvenile Diabetes Research Foundation International (grants 1-2008-1026, 5-2012-220, 17-2012-621 to MJH); The American Diabetes Association (grants 7-08-RA-106 to JPM, 7-09-BS-18 to EPB, and 7-12-BS-075 to MJH); The National Institutes of Health (grants R00DK077443 to Y-GC, R43DK85910 to JPM, R21AI088480 to EPB, R01DK080100 to XW, R01AI078713 and DP3DK098161 to MJH and 1-UL1-RR031973 The Clinical and Translational Science Institute Southeast Wisconsin); and The Children s Hospital of Wisconsin Foundation.

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  1. Y-G Chen and J P Mordes: The first two authors should be regarded as joint authors.

Authors and Affiliations

  1. The Max McGee National Research Center for Juvenile Diabetes, Children’s Research Institute of the Children’s Hospital of Wisconsin, Milwaukee, WI, USA

    Y-G Chen, H Kashmiri, M L Kaldunski, S Jia, R Geoffrey & M J Hessner

  2. Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA

    Y-G Chen, H Kashmiri, M L Kaldunski, S Jia, R Geoffrey & M J Hessner

  3. Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA

    J P Mordes

  4. Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA, USA

    E P Blankenhorn

  5. The Department of Physics, The Comprehensive Diabetes Center, The University of Alabama-Birmingham, Birmingham, AL, USA

    X Wang

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  1. Y-G Chen
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Chen, YG., Mordes, J., Blankenhorn, E. et al. Temporal induction of immunoregulatory processes coincides with age-dependent resistance to viral-induced type 1 diabetes. Genes Immun 14, 387–400 (2013). https://doi.org/10.1038/gene.2013.31

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