| 1. |
- Anderson, Per, et al.
(författare)
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Differential activation of signal transducer and activator of transcription (STAT)3 and STAT5 and induction of suppressors of cytokine signalling in T(h)1 and T(h)2 cells
- 2003
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Ingår i: International Immunology. - : Oxford University Press (OUP). - 1460-2377. ; 15:11, s. 1309-1317
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Tidskriftsartikel (refereegranskat)abstract
- Cytokines direct the differentiation of naive CD4(+) T cells into either IFN-gamma-producing T(h)1 cells or IL-4-producing T(h)2 cells. In this study, we analyzed the activation of signal transducer and activator of transcription (STAT)1, STAT3 and STAT5 (together with STAT4 and STAT6), and the expression of the recently identified suppressor of cytokine signalling (SOCS) proteins, in differentiated T(h)1 and T(h)2 cells, both before and after re-stimulation with anti-CD3 and anti-CD28. In addition to the polarized activation of STAT4 in T(h)1 cells and STAT6 in T(h)2 cells, we found that STAT3 and STAT5 are selectively activated in T(h)1 cells after differentiation. This activation of STAT3 and STAT5 was maintained after TCR re-stimulation. The selective activation of STAT3 and STAT5 in T(h)1 cells was associated with differential induction of SOCS molecules. After restimulation, SOCS1 expression was significantly increased in T(h)2 cells, but not in T(h)1 and nonpolarized 'T-h' cells. Additionally, the level of CIS was higher in T(h)2 cells compared with T(h)1 and T-h cells. In contrast, the expression of SOCS3 was higher in T(h)1 cells. The differential induction of SOCS proteins was paralleled by the differential expression of cytokines in re-stimulated T(h)1 and T(h)2 cells (IFN-gamma and IL-4/IL-13 respectively). Our results suggests that STAT3 and STAT5, possibly regulated by the SOCS proteins, may play a role in the differentiation of T-h cells, and in the maintenance of the T(h)1 and T(h)2 phenotype.
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| 2. |
- Chen, S, et al.
(författare)
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Functional association of cytokine-induced SH2 protein and protein kinase C in activated T cells
- 2003
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Ingår i: International Immunology. - : Oxford University Press (OUP). - 1460-2377. ; 15:3, s. 403-409
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Tidskriftsartikel (refereegranskat)abstract
- TCR signaling is mediated by intracellular signaling molecules and nuclear transcription factors, which are tightly regulated by interaction with regulatory proteins such as Grb2 and SLAP. We reported recently that TCR stimulation induces the expression of cytokine-induced SH2 protein (CIS). The expression of CIS promotes TCR-mediated activation. We have now found specific interactions between CIS and activated protein kinase C (PKC) alpha, beta and theta in TCR-stimulated T cells. CIS was shown by in vitro kinase assay to associate with activated PKC. In CIS-expressing T cells isolated from CIS-transgenic mice, the amount of activated PKC associated with CIS was found to increase following TCR stimulation. By immunohistochemical analysis, CIS was also found to co-localize with PKCtheta at the plasma membrane of activated T cells. In addition to the interaction and intracellular co-localization of the CIS and PKC, an increase in the activation of AP-1 and NF-kappaB was noted in CIS-expressing T cells, after stimulation by either anti-CD3/CD28 or phorbol myristate acetate + ionomycin. These results suggest that CIS regulates PKC activation, and that this may be important for the activation of both the AP-1 and NF-kappaB pathways in TCR signaling.
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| 3. |
- Li, Li, et al.
(författare)
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Insulin induces SOCS-6 expression and its binding to the p85 monomer of phosphoinositide 3-kinase, resulting in improvement in glucose metabolism
- 2004
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Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 279:33, s. 34107-34114
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Tidskriftsartikel (refereegranskat)abstract
- The suppressors of cytokine signaling ( SOCS) family is thought to act largely as a negative regulator of signaling by cytokines and some growth factors. Surprisingly, the SOCS-6 transgenics had no significant defects in the cytokine signaling and hematopoietic system but displayed significant improvements in glucose metabolism. Insulin stimulation of Akt/protein kinase B was also potentiated. Biochemical analysis showed that, after insulin stimulation, SOCS-6 interacted with the monomeric p85 subunit of class-Ia phosphoinositide ( PI) 3-kinase but not with p85/p110 dimers. Furthermore, SOCS-6 expression is transiently increased by serum and insulin in normal fibroblasts. However, both the mRNA and protein of SOCS-6 were rapidly degraded after induction by insulin. The degradation of the SOCS-6 protein was partially inhibited by a proteasome inhibitor, suggesting a proteasome-mediated degradation mechanism. In contrast, SOCS-6- associated p85 was not degraded and could be recruited to the newly synthesized SOCS-6 molecules in the presence of insulin, suggesting that SOCS-6 expression and its interaction with p85, but not the degradation, is regulated by insulin. The phenotype of SOCS-6 transgenic mice bears a striking resemblance to p85 knock-out mouse models in which glucose metabolism stimulated by insulin is significantly improved despite reduced activation of PI 3-kinase. This suggests that monomeric p85 might play a physiologically important role in attenuating signaling through PI 3-kinase-dependent pathways in unstimulated cells. Therefore, our results indicate that SOCS-6 may provide a dynamically regulated mechanism by which insulin can transiently overcome the negative effects that p85 monomers have on signaling via PI 3-kinase-dependent signaling pathways.
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| 4. |
- Xu, Hong-Tao, et al.
(författare)
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Effects of fucosylated milk of goat and mouse on Helicobacter pylori binding to Lewis b antigen
- 2004
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Ingår i: World Journal of Gastroenterology. - Beijing : WJG Press. - 1007-9327 .- 2219-2840. ; 10:14, s. 2063-2066
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Tidskriftsartikel (refereegranskat)abstract
- Aim:To evaluate the effects of animal milk containing fucosylated antigens on Helicobacter pylori (H pylon) binding to Lewis b antigen. Methods:A mammary gland expression vector containing human α1-3/4-fucosyltransferase cDNA sequences was constructed. Transient expression of human(α1-3/4-fucosyltransferase cDNA in goat mammary cell and establishment of transgenic mice were performed. The adhesion inhibitory properties of milk samples were analyzed by using Hpylori. Results: Goat milk samples were found to inhibit bacterial binding to Lewis b antigen. The highest inhibition was observed 42 h after injection of the plasmid. The binding activity of Hpylori to Lewis b antigen reduced mostly, by 83%, however milk samples from transgenic mice did not inhibit Hpylori binding to Lewis b antigen. Conclusion: The use of “humanized“ animal milk produced by the transgenic introduction of fucosylated antigen can perhaps provide an alternative therapy and preventive measure for Hpylori infection.
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| 5. |
- Eriksson, Kristina, 1962, et al.
(författare)
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Coupling of antigen to cholera toxin for dendritic cell vaccination promotes the induction of MHC class I-restricted cytotoxic T cells and the rejection of a cognate antigen-expressing model tumor.
- 2004
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Ingår i: European journal of immunology. - : Wiley. - 0014-2980 .- 1521-4141. ; 34:5, s. 1272-81
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Tidskriftsartikel (refereegranskat)abstract
- We previously demonstrated that cholera toxin (CT) is highly efficient as a combined carrier and adjuvant for dendritic cell (DC) vaccination, inducing strong Th1-dominated B cell and CD4(+) T cell responses. In this study we show that vaccination with DC pre-pulsed ex vivo with CT-conjugated OVA (OVA-CT) gives rise to OVA-specific CD8(+) T cells that produce IFN-gamma and are cytotoxic for OVA-expressing E.G7 tumor cells both in vitro and in vivo. The induction of specific CD8(+) CTL by OVA-CT-treated DC was associated with enhanced presentation of OVA peptide (SIINFEKL) on MHC class I in combination with an overall activation of the pulsed DC. Vaccination of mice with OVA-CT-pulsed DC resulted in rejection of already established MHC class I-positive, MHC class II-negative, OVA-expressing E.G7 tumors in an antigen-specific, CD8(+) T cell-dependent fashion and was associated with high numbers of tumor-infiltrating CD8(+) T cells. Conjugation of antigen to CT facilitated DC uptake of the linked antigen through the GM1 receptor-binding B subunit and induced strong activation-maturation signals through the biologically active A subunit. These results have interesting implications for DC vaccination aimed at inducing CTL immune responses.
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| 6. |
- 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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| 7. |
- Sun, Jia-Bin, 1948, et al.
(författare)
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Vaccination with dendritic cells pulsed in vitro with tumor antigen conjugated to cholera toxin efficiently induces specific tumoricidal CD8+ cytotoxic lymphocytes dependent on cyclic AMP activation of dendritic cells.
- 2004
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Ingår i: Clinical immunology (Orlando, Fla.). - : Elsevier BV. - 1521-6616. ; 112:1, s. 35-44
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Tidskriftsartikel (refereegranskat)abstract
- We investigated the development of CD8+ tumor-specific cytotoxic lymphocytes (CTL) and protection against tumor growth after vaccination with bone marrow-derived dendritic cells (DC) pulsed with a model protein ovalbumin conjugated to cholera toxin (OVA-CT) in B6 mice using E.G7 tumor cells expressing OVA(257-264) peptide (SIINFEKL) as target cells in vitro and in vivo. Vaccination with OVA-CT-pulsed DC concurrently induced strong CTL in vitro activity and anti-E.G7 tumor protection in vivo in WT, NK-depleted and CD4-deficient mice as well as in IL-12-/- and IFN-gamma-/- mice but not in CD8-deficient mice. Importantly, activation of CTL by OVA-CT-pulsed DC was dependent on CT-induced activation of adenylate cyclase and increased cAMP production by DC associated with increased expression of MHC class I and co-stimulatory molecules (CD80, CD86 and CD40). These results show that vaccination with DC pulsed with antigens (Ag) conjugated to CT induces a strong CTL response and suggest that conjugation of tumor Ag to CT for DC vaccination represents a promising approach for tumor vaccination and immunotherapy.
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| 8. |
- Turnquist, HR, et al.
(författare)
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Calreticulin binds to the alpha 1 domain of MHC class I independently of tapasin
- 2002
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Ingår i: Tissue Antigens. - : Wiley. - 0001-2815. ; 59:1, s. 18-24
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Tidskriftsartikel (refereegranskat)abstract
- Prior to binding to antigenic peptide, the major histoconipatibility complex (MHC) heavy chain associates with an assembly complex of proteins that includes calreticulin, tapasin, and the transporter associated with antigen processing (TAP). Our data show that calreticulin can bind weakly to L-d without tapasin's assistance, and that deglycosylation of the alpha1 domain results in a primary loss of binding to calreticulin rather than tapasin. We have also shown that high amounts of wild-type tapasin are still unable to associate with MHC class I in the absence of the MHC class I/calreticulin interaction, confirming the central role of calreticulin in the formation of the MHC class I assembly complex.
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