| 1. |
- Li, Suling, et al.
(författare)
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Cytokine-induced Src homology 2 protein (CIS) promotes T cell receptor-mediated proliferation and prolongs survival of activated T cells.
- 2000
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Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 191:6, s. 985-994
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Tidskriftsartikel (refereegranskat)abstract
- Members of the suppressor of cytokine signaling (SOCS) family were discovered as negative regulators of cytokine signaling by inhibition of the Janus kinase–signal transducer and activator of transcription (Jak-STAT) pathway. Among them, cytokine-induced Src homology 2 (SH2) protein (CIS) was found to inhibit the interleukin 3– and erythropietin-mediated STAT5 signaling pathway. However, involvement of SOCS proteins in other signaling pathways is still unknown. This study shows that the expression of CIS is selectively induced in T cells after T cell receptor (TCR) stimulation. In transgenic mice, with selective expression of CIS in CD4 T cells, elevated CIS strongly promotes TCR-mediated proliferation and cytokine production in vitro, and superantigen-induced T cell activation in vivo. Forced expression of CIS also prolongs survival of CD4 T cells after TCR activation. Molecular events immediately downstream from the TCR are not changed in CIS-expressing CD4 T cells, but activation of mitogen-activated protein (MAP) kinase pathways by TCR stimulation is significantly enhanced. Together with the increased MAP kinase activation, a direct interaction of CIS and protein kinase Cθ was also demonstrated. These results suggest that CIS is one of the important regulators of TCR-mediated T cell activation. The functions of CIS, enhancing TCR signaling and inhibiting cytokine signaling, may be important in the regulation of immune response and homeostasis.
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| 2. |
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| 3. |
- Paulsson, Kajsa M, et al.
(författare)
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Assembly of tapasin-associated MHC class I in the absence of the transporter associated with antigen processing (TAP)
- 2001
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Ingår i: International Immunology. - : Oxford University Press (OUP). - 0953-8178 .- 1460-2377. ; 13:1, s. 9-23
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Tidskriftsartikel (refereegranskat)abstract
- The assembly of MHC class I molecules is regulated by a multi-protein complex in the endoplasmic reticules (ER) termed the loading complex. Tapasin is suggested to be one of the molecules forming this complex on the basis of its interaction with both the transporter associated with antigen processing (TAP) and MHC class I molecules. To address whether TAP is indispensable for the processing of the assembly of tapasin-associated MHC class I molecules, we studied the association of MHC class I molecules with tapasin, the assembly of tapasin-associated MHC class I with peptides and the peptide-mediated dissociation of MHC class I from tapasin in TAP-mutant T2 cells. In the absence of TAP, MHC class I heavy chain and beta(2)-microglobulin dimers were found to be properly associated with tapasin. The stable MHC class I dimer was required for its association with tapasin in the ER. In the absence of TAP, tapasin retained MHC class I molecules much longer in the ER than in the presence of TAP. This low off-rate of MHC class I from tapasin was due to the absence of high-affinity peptides in the ER of TAP-mutant cells but not to the absence of TAP per se. The introduction of peptides into permeabilized microsomes of TAP-mutant cells led to effective loading of the peptides onto tapasin-associated MHC class I and to the subsequent dissociation of MHC class I from tapasin. These results demonstrate that regulation of the assembly of tapasin-associated MHC class I is independent of the interaction of tapasin with TAP, but is dependent upon the peptides transported by TAP.
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| 4. |
- Paulsson, Kajsa M, et al.
(författare)
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Association of tapasin and COPI provides a mechanism for the retrograde transport of major histocompatibility complex (MHC) class I molecules from the Golgi complex to the endoplasmic reticulum
- 2002
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Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 277:21, s. 18266-18271
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Tidskriftsartikel (refereegranskat)abstract
- Tapasin is a subunit of the transporter associated with antigen processing (TAP). It associates with the major histocompatibility complex (MHC) class I. We show that tapasin interacts with beta- and gamma-subunits of COPI coatomer. COPI retrieves membrane proteins from the Golgi network back to the endoplasmic reticulum (ER). The COPI subunit-associated tapasin also interacts with MHC class I molecules suggesting that tapasin acts as the cargo receptor for packing MHC class I molecules as cargo proteins into COPI-coated vesicles. In tapasin mutant cells, neither TAP nor MHC class I are detected in association with the COPI coatomer. Interestingly, tapasin-associated MHC class I molecules are antigenic peptide-receptive and detected in both the ER and the Golgi. Our data suggest that tapasin is required for the COPI vesicle-mediated retrograde transport of immature MHC class I molecules from the Golgi network to the ER.
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| 5. |
- Paulsson, K M, et al.
(författare)
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Distinct differences in association of MHC class I with endoplasmic reticulum proteins in wild-type, and beta 2-microglobulin- and TAP-deficient cell lines
- 2001
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Ingår i: International Immunology. - : Oxford University Press (OUP). - 0953-8178 .- 1460-2377. ; 13:8, s. 73-1063
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Tidskriftsartikel (refereegranskat)abstract
- In this study we have compared the interaction of human MHC class I molecules with IgG heavy chain (HC) binding protein (BiP), calnexin, calreticulin, tapasin and TAP in beta(2)-microglobulin (beta(2)m)- or TAP-deficient cells, as well as in wild-type B-LCL cells. Distinct differences between the association of HC and these endoplasmic reticulum (ER) proteins were found in the three cell lines. In the absence of beta(2)m (Daudi cells), HC associated with both BiP and calnexin. A prominent portion of HC was complexed simultaneously to both chaperones, as indicated by co-precipitation with either anti-calnexin or anti-class I antisera. In the presence of beta(2)m, but absence of TAP (T2 cells), HC could be co-precipitated with calnexin, whereas no detectable interaction with BiP could be demonstrated. This suggests that calnexin interacts with HC at a later stage than BiP. In B-LCL cells, HC-beta(2)m associated with calreticulin and tapasin, whereas no interaction with calnexin and BiP was observed. In the absence of beta(2)m, HC were rapidly degraded in the ER, while the ER retained HC were stabilized in the presence of beta(2)m, even in the absence of TAP. The dissociation of class I molecules from TAP in B-LCL cells correlated with the kinetics of appearance of class I molecules on the cell surface, suggesting that TAP retains peptide-free class I molecules in the ER. Taken together, our results suggest the model that BiP and calnexin sequentially control the folding of MHC class I, before MHC class I molecules associate with the loading complex.
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| 6. |
- Wang, P, et al.
(författare)
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Inhibition of the transcription factors AP-1 and NF-kappaB in CD4 T cells by peroxisome proliferator-activated receptor gamma ligands
- 2001
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Ingår i: International Immunopharmacology. - 1567-5769. ; 1:4, s. 12-803
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Tidskriftsartikel (refereegranskat)abstract
- The peroxisome proliferator-activated receptor gamma (PPARgamma), a member of the nuclear hormone receptor superfamily, is essential for adipocyte differentiation and glucose homeostasis. PPARgamma has been found recently to regulate macrophage activation in response to mitogens and inflammation. Our study shows PPARgamma to be preferentially expressed in the nuclei of resting T cells and to increase upon activation of T cells by either anti-CD3 and anti-CD28 or phorbol myristyl acetate (PMA). We also found the PPARgamma ligand ciglitizone to attenuate the activation of T cells by inhibiting cytokine gene expression and anti-CD3 and anti-CD28 or PMA-induced proliferative responses. Inhibition of both the proliferative response and inflammatory cytokine expression in CD4 T cells was correlated with suppression of the activated transcription factors AP1 and NF-kappaB. PPARgamma ligands also strongly inhibited SEA-induced Vbeta3 T cell activation in vivo. These results, together with previous findings of the inhibitory effect of PPARgamma ligands on activated macrophages, provide clear evidence for PPARgamma as a negative regulator of the inflammatory activation of both macrophage and T cells. PPARgamma may thus be a potential therapeutic target for the treatment of autoimmunity.
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| 7. |
- Zuo, Fanglei, et al.
(författare)
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Engineer probiotic bifidobacteria for food and biomedical applications - Current status and future prospective
- 2020
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Ingår i: Biotechnology Advances. - : Elsevier BV. - 0734-9750 .- 1873-1899. ; 45
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Forskningsöversikt (refereegranskat)abstract
- Bifidobacteria are members of the human gut microbiota and have shown to exert beneficial effects on their host. Certain strains have a long history of safe and effective use as probiotics. Due to the lack of efficient genetic tools, however, little is known about the molecular mechanisms on which these health-promoting properties are based, thus limiting the synthetic biology applications in bifidobacteria. Here, we discuss the recent development of genetic tools and their engagement in engineering bifidobacteria for food and biomedical applications, from eliminating antibiotic resistance mobile elements and improving robustness to preventing pathogen infections and delivering therapeutics for cancer treatment. In addition, we highlight the application of emerging genome engineering techniques for manipulating the bifidobacterial genome. Finally, we provide our perspective on the future development of synthetic biology techniques and programmed probiotic bifidobacteria with enhanced robustness and designer functionalities.
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