E2f1 mutation induces early onset of diabetes and Sjögren's syndrome in nonobese diabetic mice.
E2f1 is an important regulator of T cell proliferation, differentiation, and apoptosis that controls the transcription of a group of genes that are normally regulated at the G1 to S phase transition in the cell cycle. Insulin-dependent diabetes mellitus (IDDM) and Sjogren's syndrome (SS) are highly regulated autoimmune diseases that develop spontaneously in NOD mice. The aim of the present in vivo study was to explore the functional importance of the E2f1 molecule in IDDM and SS, in the context of whole animal physiology and pathophysiology, using E2f1-deficient NOD mice. For the experiment, we produced NOD mice homozygous for a nonfunctional E2f1 allele onto a NOD background. E2f1-deficient NOD mice developed an early and increased onset of diabetes as compared with their littermates. These mice also exhibited a defect in T lymphocyte development, leading to excessive numbers of mature T cells (CD4+ and CD8+), due to a maturation stage-specific defect in the apoptosis of thymocytes and peripheral T cells. We also found that they also exhibited a more rapid and increased entry into the S phase following antigenic stimulation of spleen cells and thymocytes in vitro. Furthermore, E2f1-deficient mice showed a profound decrease of immunoregulatory CD4+CD25+ T cells, while the spleen cells of NOD mice lacking E2f1 showed a significant increase of the proinflammatory cytokine IFN-gamma following antigenic stimulation in vitro. Consistent with these observations, E2f1 homozygous mutant NOD mice were highly predisposed to the development of IDDM and SS.
Department of Bacteriology, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo, Japan.
Mohammad Abdus
MA
Salam
Khairul
K
Matin
Naoko
N
Matsumoto
Yuzo
Y
Tsuha
Nobuhiro
N
Hanada
Hidenobu
H
Senpuku
D000818:Animals; D015704:CD4 Antigens / Q000032:analysis; D018797:Cell Cycle Proteins / Q000502:physiology*; D016207:Cytokines / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000502:physiology*; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology*; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D051379:Mice; D016688:Mice, Inbred NOD; D010179:Pancreas / Q000473:pathology; D015375:Receptors, Interleukin-2 / Q000032:analysis; D016196:S Phase; D012463:Saliva / Q000378:metabolism; D012859:Sjogren's Syndrome / Q000209:etiology*; D013601:T-Lymphocytes / Q000276:immunology; D013950:Thymus Gland / Q000473:pathology; D014157:Transcription Factors / Q000172:deficiency / Q000502:physiology*
D015704:CD4 Antigens; D018797:Cell Cycle Proteins; D016207:Cytokines; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; D015375:Receptors, Interleukin-2; D014157:Transcription Factors