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Heightened response
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RI
chain expression. To understand this observation further, Nambiar et al. (p. 2871
) used improved transfection procedures to introduce a FcRI-expressing plasmid into primary T cells. Their experiments demonstrated that the introduced FcRI chain replaces the TCR
chain in the TCR/CD3 complex after stimulation and confers a heightened responsiveness to the T cell. Transfected cells produced more intracellular calcium, had increased phosphorylation of protein tyrosine kinases, especially syk, and released more IL-2 than controls. In in vivo conditions where the TCR chain is lacking, FcRI chain synthesis is increased. The authors showed that in their system of forced expression of the FcRI chain, there is down regulation of expression of endogenous TCR. Overall, these experiments demonstrate that it is possible to duplicate in vitro the signaling process that occurs in an autoimmune disorder as a first step to learning how to control it. Mucus production in RSV bronchiolitis
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Dendritic cell response to bacterial DNA
The mammalian immune system recognizes and responds to unmethylated CpG motifs in bacterial DNA. At least two structurally distinct groups (the conventional, or K-type, and the A/D type) of CpG DNAs exist, each eliciting a different set of responses in human immune cells. Two papers in this issue look at the effect of CpG DNAs on dendritic cells. CpG DNAs activate immature dendritic cells through Toll-like receptor 9 (TLR9). On p. 3059
, Hemmi et al. document the effect of both conventional and A/D type CpG DNAs on murine dendritic cell subsets. Compared with conventional CpG DNAs, A/D type CpG DNAs elicited greater production of IFN-
in the B220+ subset of dendritic cells (considered the murine equivalent of human plasmacytoid dendritic cells). However, both types of CpG DNA produced similar responses in the B220- dendritic cell subset. Both conventional and A/D type CpG DNAs were shown to signal through the TLR9/MyD88 pathway. On p. 2802
, Heit et al. report that dendritic cells from TLR9-/- mice were able to endocytose a CpG-OVA conjugate, process it, and cross-present the Ag to CD8+ T cells. However, TLR9 was required for cross-priming of the CD8+ T cells, as CD8+ T cells from TLR9-/- mice injected with CpG-OVA conjugates did not generate an Ag-specific cytolytic response. These findings contribute to understanding the molecular mechanisms by which CpG DNA activates immune cells, which is essential for its possible use as a vaccine adjuvant.
Mature T cell signaling in vivo
Both the development of T cells in the thymus and the activation of mature T cells in the periphery are regulated through TCR signaling. One of the second messengers generated by TCR engagement is the lipid diacyglycerol (DAG), which can be phosphorylated by DAG kinase (DGK) to form phosphatidic acid. DAG binds to and activates Ras guanyl nucleotide release protein (RasGRP), which stimulates the Ras-ERK-AP-1 pathway by functioning as a nucleotide exchange factor for Ras. This pathway is involved in signaling the transcription of a number of genes critical for T cell development and activation. Sanjuan et al. (p. 2877
) investigated the role of DGK (the major T cell DGK isoform) in T cell activation in vivo. Using subcellular fractionation, the authors showed that both cytosolic DGK and RasGRP1 rapidly translocated to the membrane fraction after in vivo engagement of the TCR, while in vitro Ab studies showed that it was to the plasma membrane that these molecules migrated. The data add to the current understanding of this pathway of T cell signaling.
IgG2 dimers
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2 hinge contains two overlapping CXXC motifs, but because of their close spacing, the authors were unable to determine which of the Cys residues are involved in the dimer formation. Both IgG2,
and IgG2,
were shown to form dimers. Just as polymerization of IgA and IgM provides for greater avidity in binding, the ability of IgG2 to dimerize may likewise increase its avidity. Since IgG2 is the major IgG isotype elicited against carbohydrate Ags, and anti-carbohydrate Abs usually exhibit a low affinity compared with Abs specific for protein Ags, dimerization of IgG2 may allow it to bind more effectively, for example, to carbohydrates on the surface of bacteria. Vaccine adjuvants
Although a strong cellular response is required to control many infectious diseases, vaccine adjuvants currently approved for human use fail to elicit such responses. Bruna-Romero et al. (p. 3195 ) investigated the adjuvant properties of the human dendritic cell chemokine DC-CK1 in relation to malaria sporozoite immunity. Mice were injected with the immunogen (either irradiated sporozoites of the rodent malarial agent Plasmodium yoelii or recombinant adenovirus expressing P. yoelii circumsporozoite protein), with or without the adjuvant (either recombinant human DC-CK1 or recombinant human DC-CK1-expressing adenovirus). The authors showed that human DC-CK1 is chemotactic for mouse splenocytes. They found that administration of the adjuvant resulted in an enhanced Ag-specific CD8+ T cell response. In addition, the mice that received the adjuvant exhibited increased protection against subsequent infection with live P. yoelii sporozoites. DC-CK1 may therefore be an effective adjuvant for vaccines where elicitation of a strong cellular response is required.
Variety in memory T cells
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chain that lowers the affinity of the TCR for its MHC:peptide ligand. These T cells possess an effector memory phenotype yet do not exhibit immediate effector functions such as IFN- or IL-4 production. Instead, these memory-like cells require secondary TCR stimulation to produce these cytokines. Therefore, these cells do not fit strictly into either the central or effector memory groups and appear to constitute a pool of central memory-like cells that contain effector memory precursors. SDF-1 and lupus
New Zealand Black/New Zealand White (NZB/W) mice spontaneously develop an autoimmune disease that is used as a model for human systemic lupus erythematosus. NZB/W mice exhibit an abnormal expansion of an autoreactive B1a cell population in both the peritoneal cavity and spleen. Balababian et al. (p. 3392 ) studied the effect of stromal cell-derived factor-1 (SDF-1/CXCL12) on peritoneal B1a cells from New Zealand Black (NZB) and NZB/W mice. In vitro cell migration assays showed that NZB and NZB/W peritoneal B1a cells were more sensitive to SDF-1 than cells from three strains of normal mice; this effect was enhanced by IL-10. In the mouse, B1a cells are considered the major source of B cell-derived IL-10, and IL-10 is known to stimulate the growth of normal and malignant B1 cells. Treatment of young NZB/W mice with Abs against either SDF-1 or IL-10 prevented the development of autoantibodies, nephritis, and death, while administration of anti-SDF-1 mAb later in life reduced the abnormal expansion of B1a cells, inhibited autoantibody production, and reduced proteinuria and glomerular lesions. Therefore, SDF-1 appears to be an important factor in the development of autoimmunity in this mouse model and anti-SDF-1 treatment may be efficacious in treatment of systemic lupus erythematosus.
Summaries written by Kaylene J. Kenyon, Ph.D. and Dorothy L. Buchhagen, Ph.D.
Related articles in The JI:
-Chain Renders Human T Cells Hyperresponsive to TCR/CD3 Stimulation
to the Membrane: A Novel Mechanism for Ras Attenuation
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