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The Journal of Immunology is published twice each month by
The American Association of Immunologists, Inc.,
1451 Rockville Pike, Suite 650, Rockville, MD 20852
Copyright © 2003 by The American Association of
Immunologists All rights reserved.
Print ISSN: 0022-1767 Online ISSN: 1550-6606.
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J Immunol 2003; 170:2795-2796; ;
doi: 10.4049/jimmunol.170.6.2795
http://www.jimmunol.org/content/170/6/2795
OF
THE
JOURNAL IMMUNOLOGY
IN THIS ISSUE
Heightened response
T
Mucus production in RSV
bronchiolitis
espiratory syncytial
virus (RSV) infection
in infants not only results in hospitalization for immediate treatment, but has also been implicated in the development of asthma. RSV infection leads to mucus production,
an increase in Th2-type cytokines and the infiltration of eosinophils and/or T cells in the lungs. In humans, RSV infection
induces production of a number of chemokines, including
IL-8, which binds to the receptor CXCR2. In mice, CXCR2 is
the receptor for several chemokines produced upon RSV infection. Miller et al. (p. 3348) showed that CXCR2 was induced
upon RSV infection in the mouse and that anti-CXCR2 Ab
treatment led to decreased mucus production and airway hyperreactivity. This finding was confirmed using CXCR2⫺/⫺
mice. The authors showed that, in addition to its known expression on neutrophils, CXCR2 is also expressed on alveolar
R
Copyright © 2003 by The American Association of Immunologists, Inc.
Dendritic cell response to bacterial
DNA
he 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 Agspecific 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.
T
Mature T cell signaling in vivo
oth 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
B
0022-1767/03/$02.00
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he increased intracellular signaling in T
cells from patients
with systemic lupus erythematosus has been shown to be a
consequence of spontaneous
enhanced Fc⑀RI␥ chain expression. To understand this
observation further, Nambiar
et al. (p. 2871) used improved
transfection procedures to introduce a Fc⑀RI␥-expressing plasmid into primary T cells. Their experiments demonstrated that
the introduced Fc⑀RI␥ 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,
Fc⑀RI␥ chain synthesis is increased. The authors showed that in
their system of forced expression of the Fc⑀RI␥ 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.
macrophages in this mouse model of RSV infection. Hence
CXCR2 appears to have a role in mucus production, in addition to its established roles in neutrophil chemotaxis and endothelial and stromal cell proliferation.
2796
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
A
Vaccine adjuvants
lthough 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 DCCK1 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.
A
aive and memory
cells are the two major types of mature
CD4⫹ T cells found in secondary lymphoid tissue. Classification into either group is based
upon adherence to several phenotypic and functional criteria.
Memory cells have been further divided into central and
effector memory cells, based
on expression of CCR7 and L-selectin. The paper by Blander et
al. (p. 2940) describes further heterogeneity in the memory
CD4⫹ T cell population. The authors studied T cells from
L51S TCR transgenic mice, which carry a mutation in the
TCR␣ 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.
N
SDF-1 and lupus
ew 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 antiSDF-1 treatment may be efficacious in treatment of systemic
lupus erythematosus.
N
Summaries written by
Kaylene J. Kenyon, Ph.D. and
Dorothy L. Buchhagen, Ph.D.
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lthough both IgA
and IgM are known
to polymerize, covalent polymers of IgG have not
been previously observed. Yoo
et al. (p. 3134) now report that purified human IgG2 mAbs, as
well as IgG2 in human serum, form covalent dimers, apparently
via disulfide bonds in the hinge region of the molecule. The
authors used SDS-PAGE, Western blots, size exclusion FPLC
and CNBr cleavage to arrive at their conclusions. The ␥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.
Variety in memory T cells