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Turning off apoptosis
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enzi et al. (p. 1224
) looked at activation markers in parasite-infected bovine cells and in infected bovine cells that had been cured by treatment with the naphthoquinone derivative BW720c. Although procaspases 8 and 9 were detected in T. parva-infected cells, they were not cleaved until after 2 days of BW720c treatment. Infected and cured cells expressed Fas and FasL on their surfaces, but only the cured cells underwent apoptosis via induction of caspase activity. High levels of expression of FLIP and three other inhibitors of the caspase pathway were detected in T. parva-infected cells. By the third day of BW720c treatment of the infected cells, no inhibitor proteins could be found, indicating that expression of the anti-apoptotic proteins in the infected cells was highly dependent on the presence of the parasite. The findings demonstrate that T. parva is able to usurp anti-apoptotic proteins to render the cell resistant to apoptosis, thereby guaranteeing that its refuge is not destroyed. Interfering with IFN
Death in individuals suffering from African trypanosomiasis results from a progressive parasite-induced immunosuppression. Although soluble membrane molecules released from the trypanosome are known to be involved in macrophage activation, their role in immunosuppression is unclear. Coller et al. (p. 1466
) measured serum levels of glycosylinositolphosphate soluble variant surface glycoprotein (GIP-sVSG) from C57BL/10 mice infected with the protozoan parasite Trypanosoma brucei. They found that levels of GIP-sVSG peaked early (6 days) in infection, subsided, and then returned to the early high level late (after 35 days) in infection. Serum levels of IFN-
peaked at 6 days but remained very low beyond that time. Mouse macrophages were treated in vitro with GIP-sVSG molecules and IFN- at doses that corresponded to serum concentrations found in infected animals during the first days of infection. Pretreatment of the cells with IFN- followed by stimulation with GIP-sVSG resulted in higher levels of transcription of TNF-
, IL-6, IL-12p40, and iNOS than in untreated cells or in cells treated with either GIP-sVSG or IFN- alone. In contrast, pretreatment of cells with GIP-sVSG followed by IFN- treatment resulted in reduced expression of those same molecules compared with the controls. IFN- at levels five or more times the physiological dose overcame the inhibition of NO production by GIP-sVSG. Western analyses showed that GIP-sVSG inhibited IFN--dependent STAT1 phosphorylation. The data indicate that the parasite T. brucei can overcome the host immune response by interfering with the actions of IFN-.
Blocking GVHD
Programmed death-1 (PD-1), a member of the B7:CD28 superfamily, is expressed on a number of organs that are the target of graft-vs-host disease (GVHD). However, the effect of the interaction of PD-1 with PD-L1, one of its ligands, on T cell responses and on the regulation of GVHD has not been examined. Blazar et al. (p. 1272
) induced GVHD in lethally irradiated B10.BR mice by injection of C57BL/6 (B6) bone marrow cells depleted of T cells and supplemented with B6 splenocytes. The PD-1 pathway was blocked by coadministration of either a PD-L1 fusion protein or an anti-PD-1 mAb. Both PD-1 pathway blockades accelerated GVHD-induced mortality compared with GVHD-induced mice given an irrelevant fusion protein or an irrelevant mAb. Injection of splenocytes or separated CD4+ T or CD8+ T cells from B6-PD-1-/- mice into irradiated B10.BR hosts also accelerated GVHD over injection of similar cell populations from B6 wild-type mice. The substitution of B6 FasL-/- or B6 perforin-/- splenocytes for those from wild-type B6 mice did not increase PD-1 mediated GVHD. IFN- levels were higher in MLR cultures containing B6-PD-1-/- T cells than in wild-type B6 cells, and were higher in the sera of anti-PD-1-mAb-treated GVHD animals vs controls. The results show that the PD-1/PD-L1 pathway is involved in down-regulating both T cell responses and IFN- production in vivo. The authors propose ligation of the PD-1 receptor as an approach to preventing GVHD.
A regulator of IL-12 signaling
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1 and a T cell lymphoma cDNA library. The IL-12R1 cDNA "bait" protein bound to a protein expressed from mouse sphingosine kinase 2 (SPHK2) cDNA. IL-12R1 and SPHK2 were coprecipitated by their respective mAbs from lysates of cells cotransfected with vectors expressing the two full-length proteins. Using deletion mutants, the regions of interaction were mapped to the proline-rich domain in SPHK2 and to two domains in the IL-12R1 cytoplasmic region. Functional significance of the interaction was demonstrated by transient transfections and reporter gene assays. IL-12 costimulation of T cells cotransfected with the SPHK2 and IL-12R1 constructs induced transcriptional activation of a STAT4-responsive reporter construct. IL-12-induced IFN- production was suppressed in T cells transfected with an expression vector containing a double-negative mutant of SPHK2, whereas transfection with wild-type SPHK2 enhanced IFN- production under the same conditions. Proliferative activities of the transfected cells were unaffected by the transfected molecules. The involvement of SPHK2 adds another layer of complexity to the mechanism of IL-12 signaling. Transcriptional control of CD4+T cell responses
Scurfin, the protein product of the FoxP3 gene, a member of the forkhead/winged-helix family, has been shown to act as a transcriptional repressor. Mutations in FoxP3 lead to autoimmunity and hyperresponsive CD4+ T cells, whereas over-expression of scurfin in FoxP3 transgenic (Tg) mice results in a decrease in CD4+ and CD8+ T cells. However, the ability of T or B cells from FoxP3 Tg mice to respond to an immunologic challenge is unknown. Kasprowicz et al. (p. 1216
) found that FoxP3 Tg mice had 2- and 5-fold less serum IgG1 and IgG2a, respectively, than normal littermate control (NLC) mice. Immunization of FoxP3 Tg mice with a T cell-dependent Ag resulted in weak primary and secondary Ab responses. B cells and CD4+T cells were purified from immunized NLC or FoxP3 Tg mice. Levels of IgG1 and IgG2a produced by mixtures of the cells in the presence of Ag were 2- to 4-fold lower when FoxP3 Tg CD4+ T cells were used whether the B cells were of NLC or FoxP3 Tg origin. Adoptive transfer of mixtures of CD4+ T and B cells into RAG-/- mice showed that immunoglobulin levels after Ag challenge were reduced only when FoxP3 Tg CD4+T cells were used, suggesting that the defect was in FoxP3 Tg CD4+T cell help. FoxP3 Tg CD4+T cells were unable to up-regulate CD40L or CD69 when stimulated in vitro. Cells from immunized FoxP3 Tg mice produced lower levels of IFN- following in vitro stimulation compared with T cells from immunized NLC mice. The data demonstrate that overexpression of scurfin results in a variety of CD4+ T cell defects that lead to a reduction in Ab production.
Using altered MHC anchor peptides to treat EAE
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. None of the B6 mice immunized with 45D developed EAE, whereas all of the B6 mice immunized with MOG 35–55 or 47A did. MOG 35–55 specific T cells stimulated with MOG 35–55 in vitro adoptively transferred EAE to all injected B6 mice, but no EAE developed in B6 mice injected with MOG 35–55 specific T cells treated in vitro with 45D. The results indicate that use of a MHC anchor substituted peptide is more effective in treating EAE than a peptide mutated in TCR contact residues. Complement(ary) killing of tumor cells
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Summaries written by Dorothy L. Buchhagen, Ph.D.
Related articles in The JI:
-Dependent Mechanism
1 Cytoplasmic Region
-Induced Nitric Oxide Production Via Reduction in STAT1 Phosphorylation in African Trypanosomiasis
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