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Deficiency of Nuclear Factor-κB c-Rel Accelerates the Development of Autoimmune Diabetes in NOD Mice

Ramakrishnan, Parameswaran and Yui, Mary A. and Tomalka, Jeffrey A. and Majumdar, Devdoot and Parameswaran, Reshmi and Baltimore, David (2016) Deficiency of Nuclear Factor-κB c-Rel Accelerates the Development of Autoimmune Diabetes in NOD Mice. Diabetes, 65 (8). pp. 2367-2379. ISSN 0012-1797. PMCID PMC4955991. doi:10.2337/db15-1607.

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The nuclear factor-κB protein c-Rel plays a critical role in controlling autoimmunity. c-Rel–deficient mice are resistant to streptozotocin-induced diabetes, a drug-induced model of autoimmune diabetes. We generated c-Rel–deficient NOD mice to examine the role of c-Rel in the development of spontaneous autoimmune diabetes. We found that both CD4^+ and CD8^+ T cells from c-Rel–deficient NOD mice showed significantly decreased T-cell receptor–induced IL-2, IFN-γ, and GM-CSF expression. Despite compromised T-cell function, c-Rel deficiency dramatically accelerated insulitis and hyperglycemia in NOD mice along with a substantial reduction in T-regulatory (Treg) cell numbers. Supplementation of isogenic c-Rel–competent Treg cells from prediabetic NOD mice reversed the accelerated diabetes development in c-Rel–deficient NOD mice. The results suggest that c-Rel–dependent Treg cell function is critical in suppressing early-onset autoimmune diabetogenesis in NOD mice. This study provides a novel natural system to study autoimmune diabetes pathogenesis and reveals a previously unknown c-Rel–dependent mechanistic difference between chemically induced and spontaneous diabetogenesis. The study also reveals a unique protective role of c-Rel in autoimmune diabetes, which is distinct from other T-cell–dependent autoimmune diseases such as arthritis and experimental autoimmune encephalomyelitis, where c-Rel promotes autoimmunity.

Item Type:Article
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URLURL TypeDescription Data CentralArticle
Ramakrishnan, Parameswaran0000-0002-1314-827X
Yui, Mary A.0000-0002-3136-2181
Baltimore, David0000-0001-8723-8190
Alternate Title:Deficiency of NF-kappaB c-Rel Accelerates the Development of Autoimmune Diabetes in Non-Obese Diabetic Mice
Additional Information:© 2016 American Diabetes Association. Received 24 November 2015 and accepted 15 May 2016. The authors thank Hsiou-Chi Liou, Cornell University, for providing c-Rel knockout mice; Diane Mathis and Christophe Benoist, Harvard Medical School, for providing FOXP3-IRES-GFP mice; the California Institute of Technology and Case Western Reserve University animal facilities; Ni Feng, California Institute of Technology, for flow cytometry; and Daniel Kahn and Jevgenij Raskatov, California Institute of Technology, and Timothy Kern, Case Western Reserve University, for insightful discussions. This work was initially supported by National Institute of General Medical Sciences grant 2R01-GM-039458 to D.B. and later by Mizutani Foundation for Glycoscience grant 120022, the Clinical and Translational Science Collaborative of Cleveland, grant CTSC UL1-TR-000439 from the National Center for Advancing Translational Sciences, and National Institute of Allergy and Infectious Diseases grant 1R01-AI-116730-01A1 to P.R. M.A.Y. was supported by National Institutes of Health grant AI-64590. J.A.T. was supported by an American Association of Immunologists (AAI) Careers in Immunology Fellowship to P.R. No potential conflicts of interest relevant to this article were reported. Author Contributions: P.R. contributed to the study conception and design, data research, and writing of the manuscript. M.A.Y. contributed to the data research, discussion, and editing of the manuscript. J.A.T., D.M., and R.P. contributed to the data research. D.B. contributed to the data interpretation, discussion, and review and editing of the manuscript. P.R. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Funding AgencyGrant Number
Mizutani Foundation for Glycoscience120022
Clinical and Translational Science Collaborative of ClevelandUNSPECIFIED
American Association of ImmunologistsUNSPECIFIED
Issue or Number:8
PubMed Central ID:PMC4955991
Record Number:CaltechAUTHORS:20160525-150035453
Persistent URL:
Official Citation:Deficiency of Nuclear Factor-κB c-Rel Accelerates the Development of Autoimmune Diabetes in NOD Mice Parameswaran Ramakrishnan, Mary A. Yui, Jeffrey A. Tomalka, Devdoot Majumdar, Reshmi Parameswaran, David Baltimore Diabetes Aug 2016, 65 (8) 2367-2379; DOI: 10.2337/db15-1607
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:67366
Deposited By: Tony Diaz
Deposited On:26 May 2016 16:27
Last Modified:11 Nov 2021 00:31

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