E2f1Mutation Induces Early Onset of Diabetes and Sjögren’s Syndrome in Nonobese Diabetic Mice

Abstract

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 Sjögren’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-γ following antigenic stimulation in vitro. Consistent with these observations, E2f1 homozygous mutant NOD mice were highly predisposed to the development of IDDM and SS.

STIM1 and STIM2 protein deficiency in T lymphocytes underlies development of the exocrine gland autoimmune disease, Sjögren's syndrome

“…Synthesis of IL-2, a critical factor in Treg differentiation and activation, in T cells is dependent on activation of NFAT by SOCE (34). NOD mice, a frequently used mouse model for pSS, display a reduction in IL-2 together with an age-dependent reduction in Treg population and onset of SS (23,24,35). IL-2 KO and IL-2Rα KO mice, which exhibit deficient Treg populations, develop severe lymphocyte infiltration in the salivary and lacrimal glands with decreased secretory function (21,22).…”

“…Based on the autoimmune phenotype of the STIM1 and STIM2 double-knockout (DKO) mice and the generation of pSS-like disease in several mouse models with decreased Treg function (19)(20)(21)(22)(23)(24), we assessed a possible link between STIM1 and STIM2 deficiency in T cells and autoimmunopathy of the salivary glands. Here we report that DKO mice display spontaneous and progressive submandibular gland inflammation (within 3 mo), comparable to that seen in pSS patients with severe salivary gland damage.…”

The Tumor Suppressor ARF Regulates Innate Immune Responses in Mice

“…Moreover, E2F1 acts as a suppressor of dendritic cell maturation, inhibiting the activation of several major signaling pathways, including ERK1/2, Akt, and NF-kB p65 (28). Finally, mice lacking E2F1 are reported to be more susceptible to the development of autoimmune syndromes (25)(26)(27). Supporting the role of E2F1 as an inflammatory suppressor in ARF 2/2 macrophages, LPS treatment of ARF 2/2 cells upregulates E2F1 and enhances physical interaction between the p65 subunit of NF-kB and E2F1, inhibiting the formation of functional NF-kB (p65/p50) (43).…”

“…The transcription factor E2F1 is one of the key proteins in the regulation of the G 1 /S phase transition, acting as a critical regulator of cell survival and proliferation (23). In addition, E2F1 has been shown to regulate a wide range of genes in response to inflammatory stimulation of macrophages and to contribute to T cell activation in response to pathogens, suggesting that E2F1 may act as an antiinflammatory or immunosuppressive transcription factor (24)(25)(26)(27)(28).…”

Transcription Factor E2F1 Suppresses Dendritic Cell Maturation

“…In this regard, E2F1 has previously been shown to suppress TNF-ainduced activation of human aortic endothelial cells by inhibiting NF-kB activation and translocation (38). Furthermore, mice lacking E2F1 are reported to be more susceptible to the development of autoimmune syndromes (23,39,40). In these mice, there are excessive numbers of mature CD4 and CD8 T cells and reduced number of CD4 + /CD25 + regulatory T cells, which is thought to be to the result of a defect in the apoptosis of T cells (23,40).…”