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C3a and its receptor in demyelinating disease
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Dendritic cell survival depends on bcl-xL
Dendritic cells (DCs) process foreign Ag in the periphery to differentiate into professional APCs that migrate to draining lymph nodes (dLNs). A robust T cell response is dependent upon the longevity of Ag-bearing DCs. Hon et al. (p. 4425 ) looked at the role of the antiapoptotic protein, bcl-xL, in prolonging the life of APCs in cre-lox conditional bcl-x knockout mice (bcl-xfl/fl). Gene gun immunization of a plasmid DNA vaccine encoding cre recombinase into the skin of bcl-xfl/fl mice resulted in deletion of the bcl-x gene in skin cells and in mature DCs isolated from dLNs 2.5 days after immunization. DCs from dLNs of mice immunized with dual expression plasmids encoding cre recombinase and OVA had a reduced ability to induce OVA-specific T cell proliferation. Serum levels of virus-specific Ab were lower in mice immunized with dual expression plasmids encoding cre recombinase and an influenza virus protein. Bcl-xfl/fl mice immunized with a plasmid encoding both lacZ and cre recombinase, and wild-type mice immunized with a plasmid containing a small interfering RNA oligonucleotide specific for bcl-xL isoform of bcl-x, had reduced numbers of mature DCs and increased numbers of apoptotic DCs in their dLNs. There were no differences in migration of DCs from the immunization site to dLNs between experimental or control animals. The number of mature DCs in the dLNs of bcl-xfl/fl mice immunized with plasmids encoding cre recombinase was restored to preimmunization levels by coimmunization with a plasmid encoding bcl-xL cDNA. The data indicate that bcl-xL is critical in maintaining the longevity of Ag-bearing DC after their migration to the dLN.
Boosting antitumor T cell responses in old mice
It is unclear why cancer incidence increases with advancing age. Lustgarten et al. (p. 4510 ) found 100% mortality of old (18- to 22-mo-old) and young (2- to 3-mo-old) BALB/c mice injected with pre-B cell lymphoma cells. All of the young, but none of the old, animals survived following injection with tumor cells transduced with the enhanced GFP (EGFP) gene that acted as a tumor Ag. Tumor cells expressing both EGFP and a transduced CD80 were rejected by all of the old and the young mice; however, only the young animals were able to reject a challenge with wild-type tumor cells 30 days later. Four weekly injections of anti-OX40 mAb following immunization with tumor cells expressing EGFP or EGFP and CD80 increased the ability of old mice to survive challenge with wild-type tumor cells 90 days later to 40% and 100%, respectively. Splenic CD8+ T cells from old mice immunized with tumor cells expressing both EGFP and CD80 had increased MHC multimer binding compared with CD8+ T cells isolated from mice immunized with tumor cells expressing EGFP alone. Addition of anti-OX40 mAb further increased the number of tetramer-binding cells in both young and old mice. Spleen cells from young mice immunized with tumor cells expressing EGFP, with or without anti-OX40 mAb, had strong cytotoxic responses against tumor cells, whereas cytotoxic activity of spleen cells from old mice was seen only in animals that received anti-OX40 mAb during immunizations. The data show that old mice are able to mount effective CD8+ T cell antitumor responses and protective memory if provided with costimulatory signals.
Killer cell Ig-like receptors, HLA-C ligands, and psoriatic arthritis
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Control of Fc
R1 expression in mast cells
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R1. These interactions can lead to either receptor internalization or up-regulation. However, it is not clear how signaling pathways control FcR1 expression. Kitaura et al. (p. 4317
) examined FcR1 surface expression on mouse mast cells in three stimulation models, namely, IgE, IgE plus Ag, and IgE plus anti-IgE Ab. Low concentrations of highly cytokinergic (HC) IgE up-regulated the receptor, but high concentrations resulted in receptor internalization. In contrast, increasing concentrations of poorly cytokinergic IgE increased receptor surface expression, but only receptor internalization was blocked by a monovalent hapten that disaggregated receptors. Inhibition of, or deficiencies in, a variety of serine/threonine kinases did not alter IgE-induced receptor up-regulation. Among mast cells from several strains of mice deficient in protein tyrosine kinases, Lyn-deficient cells exhibited defective receptor internalization induced by high concentrations of HC IgE and by IgE plus anti-IgE Ab. Fyn-deficient cells were less defective for IgE plus Ag-induced receptor internalization. Pervanadate, an inhibitor of protein tyrosine kinases, corrected the IgE-induced receptor internalization defect in Lyn-deficient cells. Increased initial velocity of receptor internalization and higher mast cell survival rates were seen with IgE plus anti-IgE Ab. Release of histamine and IL-6 required nearly 10-fold higher concentrations of IgE or Ag and was Syk-dependent. The data suggest that IgE-induced regulation of FcR1 levels has a different signaling requirement than other mast cell activating events. Activated plasmacytoid dendritic cells induce CD4+CD25+ regulatory T cells
Plasmacytoid dendritic cells (PDCs) are involved in immunological tolerance. Although PDCs can be activated by CpG oligodeoxynucleotides (ODNs), it is unclear whether the PDCs are involved in the generation of CD4+CD25+ regulatory T cells (Tregs). Moseman et al. (p. 4433
) found that PDC-induced proliferation of allogeneic naive human CD4+ T cells was increased by prior exposure of the PDCs to CpG-B ODNs. However, those ODN-exposed CD4+ T cells did not respond to the priming Ag in secondary MLR cultures and suppressed naive T cell proliferation in primary MLR cultures. Addition of ODNs to cultures of naive CD4+ T cells plus PDCs significantly increased Treg cell numbers and enhanced production of typical Treg cytokines (IL-10, TGF-
, IFN-
, IL-6). Tregs did not develop in cultures lacking PDCs or when the PDCs and CD4+ T cells were separated by trans-wells. High levels of TLR 9 mRNA were detected by RT-PCR in PDCs exposed to ODN, and high levels of forkhead transcription factor, Foxp3, mRNA were transcribed by Tregs generated by PDC and ODN. Tregs induced by ODN-activated PDCs suppressed proliferation of autologous and allogeneic T cells in response to the primed and other alloantigens. This Treg suppression was induced by PDC activated by three classes of CpG ODN (A, B, and C). The results suggest that CpG ODN immunostimulation of human PDCs through TLR9 could have application in the induction and maintenance of Treg-mediated immune tolerance.
Ikaros control of thymic T cell development
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Summaries written by Dorothy L. Buchhagen, Ph.D.
Related articles in The JI:
Receptor I Signals for Receptor Up-Regulation and Internalization from Degranulation, Cytokine Production, and Survival
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