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IL-6/IL-6R and rheumatoid arthritis
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A better DNA vaccine
Two strategies to enhance the anti-tumor activity of dendritic cells (DC) are to link a specific Ag to an intracellular targeted protein and to cotransfect DNAs encoding a tumor Ag and an anti-apoptotic protein. Both of these approaches have been used successfully by T.-C. Wu and colleagues to enhance the CD8+ T cell response to human papillomavirus (HPV) 16 E7 Ag. In their paper on p. 2970 , Kim et al. combined these strategies. Mice covaccinated with a plasmid DNA encoding the anti-apoptotic protein, BCL-xL, and with one encoding E7 linked to lysosome-associated membrane protein 1 (E7/LAMP-1) had the greatest fold increase of E7-specific CD8+ T cells of three combinations tested. Mutation of the BCL-xL DNA reduced the high functional avidity of the responding CD8+ T cells to the level seen by covaccination with empty vector. CD4L knockout mice vaccinated with E7/LAMP-1 and BCL-xL DNAs had a weaker response than similarly vaccinated wild-type mice but generated 2-fold more E7-specific CD8+ T cells than wild-type mice vaccinated with E7/LAMP-1 alone. Mice vaccinated with the DNA mixture developed fewer HPV tumor nodules than unvaccinated mice or mice vaccinated with E7/LAMP-1 alone, and the anti-tumor response was still strong at seven weeks after vaccination. The data indicate that a combined approach that prolongs the life of dendritic cells enhances anti-tumor immunity even in the absence of CD4+ T cells.
Reactive oxygen species in Ag presentation
Low concentrations of reactive oxygen species (ROS) can act as second messengers in cellular signaling via redox regulation of molecular pathways in both dendritic cells (DC) and T cells. Matsue et al. (p. 3010 ) examined the pharmacological impact of ebselen, a seleno-organic compound with multifunctional antioxidant activities, on DC and T cells. Ebselen reduced the growth, survival, and cytokine production of activated murine CD4+ T cells and DC lines. A cell permeant, oxidation-sensitive dye fluoresced in activated DC, demonstrating that stimulated cells generated ROS. Ebselen inhibited fluorescence in both bone marrow-derived DC and CD4+ T cells cocultured with a specific Ag. Proliferation and cytokine production by both cell types was also suppressed by the antioxidant. In vivo, ebselen significantly reduced the ear swelling in hapten-sensitized mice challenged with the same hapten compared with animals given vehicle alone. Oral administration of ebselen during the sensitization and postchallenge phases was most effective. The authors conclude that low concentrations of ROS are important in bidirectional DC-T interactions during Ag presentation. They propose that ebselen could be beneficial in preventing inflammatory skin reactions.
T cell-mediated hepatitis
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The immune synapse and T cell fate
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Non-immune function of MHC proteins
Decreased expression of MHC class I glycoproteins is often associated with the ability of malignant cells to escape immune surveillance. Yet the molecular mechanism by which a lack of MHC class I molecules contributes to the malignant phenotype is unclear. Assa-Kunik et al. (p. 2945 ) examined H-2k-deficient and H-2k-expressing clones derived from the mouse B16B6 melanoma. Clones that had gained the capacity to express H-2k, either by transfection or by reversion, were non-tumorigenic, and they exhibited binding of insulin to its membrane-associated receptor (IR). Clones expressing H-2k induced tumors; they did not bind insulin and the IR was retained in intracellular compartments. IR was differentially glycosylated and poorly phosphorylated in H-2k-deficient clones compared with the IR in H-2k-expressing clones. Addition of insulin to H-2k-expressing clones maintained in serum-free medium reduced the percentage of apoptotic cells and increased intracellular activity of the protein kinase B (PKB)/Akt kinase. H-2k-deficient clones, able to survive in serum-free medium without insulin, had high constitutive activation of PKB/Akt. An inhibitor of an up-stream regulator of PKB/Akt decreased the intracellular levels of the enzyme and induced apoptosis in the cells. The authors propose that loss of expression of H-2k promotes malignancy through a decreased demand for insulin via deregulation of PKB/Akt activity.
Vaccination with heat-killed bacteria
Vaccination with live microorganisms induces specific effector and memory T cells. However, there are conflicting reports about the relationship between effector and memory T cells and about the ability of heat-killed microorganisms to elicit effector responses. Lefrançois et al. (p. 2832
) examined T cell responses in C57BL/6 mice immunized with live Listeria monocytogenes (LM) or heat-killed LM (HKLM). A recombinant LM virus expressing a truncated OVA protein was used to generate CD8+ T cells that could be detected by an H-2Kb tetramer containing an OVA peptide. Immunization with LM and HKLM resulted in similar levels of activated CD8+ T cells in the lung and spleen at day five. The T cell response to LM infection continued to increase, whereas the response to HKLM rapidly decreased. The number of Ag-specific memory cells detected in the lung and spleen three weeks after immunization was substantially higher in LM immunized animals. CD8+ T cells from HKLM-immunized mice challenged with LM were able to kill the bacteria at a higher level and earlier than non-immunized mice but at a lower level and later compared with LM-immunized mice. CD8+ T cells from the HKLM-immunized animals had an early, brief clonal expansion and lytic activity after peptide challenge in vivo and produced IFN-
after peptide challenge in vitro. Thus, a heat-killed bacteria vaccine induces a small number of effector CD8+ T cells that develop into memory cells.
Summaries written by Dorothy L. Buchhagen, Ph.D.
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