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Yu-Wen Su,
Zhenyue Hao,
Atsushi Hirao,
Kazuo Yamamoto,
Wen-Jye Lin,
Ashley Young,
Gordon S Duncan,
Hiroki Yoshida,
Andrew Wakeham,
Philipp A Lang,
Kiichi Murakami,
Heiko Hermeking,
Bert Vogelstein, Pamela Ohashi,
Tak W Mak
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ABSTRACT: 14-3-3σ regulates cytokinesis and cell cycle arrest induced by DNA damage but its role in the immune system is unknown. Using gene-targeted 14-3-3σ-deficient (i.e., KO) mice, we studied the role of 14-3-3σ in B-cell functions. Total numbers of B cells were reduced by spontaneous apoptosis of peripheral B cells. Upon B-cell antigen receptor engagement in vitro, KO B cells did not proliferate properly or up-regulate CD86. In response to T cell-independent antigens, KO B cells showed poor secretion of antigen-specific IgM. This deficit led to increased lethality of KO mice after vesicular stomatitis virus infection. KO B cells showed elevated total FOXO transcriptional activity but also increased FOXO1 degradation. Coimmunoprecipitation revealed that endogenous 14-3-3σ protein formed a complex with FOXO1 protein. Our results suggest that 14-3-3σ maintains FOXO1 at a consistent level critical for normal B-cell antigen receptor signaling and B-cell survival.
Proceedings of the National Academy of Sciences 01/2011; 108(4):1555-60. · 9.68 Impact Factor
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Hien Chau,
Veronica Wong,
Nien-Jung Chen,
Huey-Lan Huang,
Wen-Jye Lin,
Christine Mirtsos,
Alisha R Elford,
Madeleine Bonnard,
Andrew Wakeham,
Annick Itie You-Ten,
Bénédicte Lemmers,
Leonardo Salmena,
Marc Pellegrini,
Razq Hakem,
Tak W Mak, Pamela Ohashi,
Wen-Chen Yeh
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ABSTRACT: Fas-associated death domain (FADD) and caspase-8 are key signal transducers for death receptor-induced apoptosis, whereas cellular FLICE-inhibitory protein (cFLIP) antagonizes this process. Interestingly, FADD and caspase-8 also play a role in T cell development and T cell receptor (TCR)-mediated proliferative responses. To investigate the underlying mechanism, we generated cFLIP-deficient T cells by reconstituting Rag-/- blastocysts with cFLIP-deficient embryonic stem cells. These Rag chimeric mutant mice (rcFLIP-/-) had severely reduced numbers of T cells in the thymus, lymph nodes, and spleen, although mature T lymphocytes did develop. Similar to FADD- or caspase-8-deficient cells, rcFLIP-/- T cells were impaired in proliferation in response to TCR stimulation. Further investigation revealed that cFLIP is required for T cell survival, as well as T cell cycling in response to TCR stimulation. Interestingly, some signaling pathways from the TCR complex appeared competent, as CD3 plus CD28 cross-linking was capable of activating the ERK pathway in rcFLIP-/- T cells. We demonstrate an essential role for cFLIP in T cell function.
Journal of Experimental Medicine 09/2005; 202(3):405-13. · 13.85 Impact Factor
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Zhenyue Hao,
Gordon S Duncan,
Chia-Che Chang,
Andrew Elia,
Min Fang,
Andrew Wakeham,
Hitoshi Okada,
Thomas Calzascia,
YingJu Jang,
Annick You-Ten,
Wen-Chen Yeh, Pamela Ohashi,
Xiaodong Wang,
Tak W Mak
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ABSTRACT: As components of the apoptosome, a caspase-activating complex, cytochrome c (Cyt c) and Apaf-1 are thought to play critical roles during apoptosis. Due to the obligate function of Cyt c in electron transport, its requirement for apoptosis in animals has been difficult to establish. We generated "knockin" mice expressing a mutant Cyt c (KA allele), which retains normal electron transfer function but fails to activate Apaf-1. Most KA/KA mice displayed embryonic or perinatal lethality caused by defects in the central nervous system, and surviving mice exhibited impaired lymphocyte homeostasis. Although fibroblasts from the KA/KA mice were resistant to apoptosis, their thymocytes were markedly more sensitive to death stimuli than Apaf-1(-/-) thymocytes. Upon treatment with gamma irradiation, procaspases were efficiently activated in apoptotic KA/KA thymocytes, but Apaf-1 oligomerization was not observed. These studies indicate the existence of a Cyt c- and apoptosome-independent but Apaf-1-dependent mechanism(s) for caspase activation.
Cell 06/2005; 121(4):579-91. · 32.40 Impact Factor
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Myung-Shin Jeon,
Alex Atfield,
K Venuprasad,
Connie Krawczyk,
Renu Sarao,
Chris Elly,
Chun Yang,
Sudha Arya,
Kurt Bachmaier,
Leon Su,
Dennis Bouchard,
Russel Jones,
Mathew Gronski, Pamela Ohashi,
Teiji Wada,
Debra Bloom,
C Garrison Fathman,
Yun-Cai Liu,
Josef M Penninger
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ABSTRACT: Antigen-specific immunotolerance limits the expansion of self-reactive T cells involved in autoimmune diseases. Here, we show that the E3 ubiquitin ligase Cbl-b is upregulated in T cells after tolerizing signals. Loss of Cbl-b in mice results in impaired induction of T cell tolerance both in vitro and in vivo. Importantly, rechallenge of Cbl-b mutant mice with the tolerizing antigen results in massive lethality. Moreover, ablation of Cbl-b resulted in exacerbated autoimmunity. Mechanistically, loss of Cbl-b rescues reduced calcium mobilization of anergic T cells, which was attributed to Cbl-b-mediated regulation of PLCgamma-1 phosphorylation. Our results show a critical role for Cbl-b in the regulation of peripheral tolerance and anergy of T cells.
Immunity 09/2004; 21(2):167-77. · 21.64 Impact Factor
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Shawn Winer,
Hubert Tsui,
Ambrose Lau,
Aihua Song,
Xiaomao Li,
Roy K Cheung,
Anastazia Sampson,
Fatemeh Afifiyan,
Alisha Elford,
George Jackowski,
Dorothy J Becker,
Pere Santamaria, Pamela Ohashi,
H-Michael Dosch
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ABSTRACT: Pancreatic islets of Langerhans are enveloped by peri-islet Schwann cells (pSC), which express glial fibrillary acidic protein (GFAP) and S100beta. pSC-autoreactive T- and B-cell responses arise in 3- to 4-week-old diabetes-prone non-obese diabetic (NOD) mice, followed by progressive pSC destruction before detectable beta-cell death. Humans with probable prediabetes generate similar autoreactivities, and autoantibodies in islet-cell autoantibody (lCA) -positive sera co-localize to pSC. Moreover, GFAP-specific NOD T-cell lines transferred pathogenic peri-insulitis to NOD/severe combined immunodeficient (NOD/SCID) mice, and immunotherapy with GFAP or S100beta prevented diabetes. pSC survived in rat insulin promoter Iymphocytic choriomeningitis virus (rip-LCMV) glycoprotein/CD8+ T-cell receptor(gp) double-transgenic mice with virus-induced diabetes, suggesting that pSC death is not an obligate consequence of local inflammation and beta-cell destruction. However, pSC were deleted in spontaneously diabetic NOD mice carrying the CD8+/8.3 T-cell receptor transgene, a T cell receptor commonly expressed in earliest islet infiltrates. Autoimmune targeting of pancreatic nervous system tissue elements seems to be an integral, early part of natural type 1 diabetes.
Nature Medicine 03/2003; 9(2):198-205. · 22.46 Impact Factor
