title: Deficiency of Nuclear Factor-κB c-Rel Accelerates the Development of Autoimmune Diabetes in NOD Mice.
abstract: 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.
authors.affiliation: Department of Pathology, School of Medicine, Case Western Reserve University, and University Hospitals Case Medical Center, Cleveland, OH pxr150@case.edu baltimo@caltech.edu.
authors.forename: Parameswaran
authors.initials: P
authors.lastname: Ramakrishnan
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA.
authors.forename: Mary A
authors.initials: MA
authors.lastname: Yui
authors.affiliation: Department of Pathology, School of Medicine, Case Western Reserve University, and University Hospitals Case Medical Center, Cleveland, OH.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Tomalka
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA.
authors.forename: Devdoot
authors.initials: D
authors.lastname: Majumdar
authors.affiliation: Department of Pathology, School of Medicine, Case Western Reserve University, and University Hospitals Case Medical Center, Cleveland, OH.
authors.forename: Reshmi
authors.initials: R
authors.lastname: Parameswaran
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA pxr150@case.edu baltimo@caltech.edu.
authors.forename: David
authors.initials: D
authors.lastname: Baltimore
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D049109:Cell Proliferation / Q000235:genetics / Q000502:physiology; D016207:Cytokines / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016328:NF-kappa B / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D010179:Pancreas / Q000378:metabolism; D020569:Proto-Oncogene Proteins c-rel / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism
chemical_list: D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D016328:NF-kappa B; D020569:Proto-Oncogene Proteins c-rel