The Journal of Immunology, 2003, 170: 665-666.
Copyright © 2003 by The American Association of Immunologists
IN THIS ISSUE
You’re only as old as ... ?
The immune
response is known to change as a person ages and is influenced by
chemokines and their receptors, which contribute to the recruitment of
lymphocytes and APCs to a particular site. Mo et al. (p. 895
) used DNA
microarrays, ribonuclease protection assays, protein analysis and
functional assays to examine the expression of chemokine receptors in
CD4+ T cell subsets in aged (20–22 mo old) compared
to young (3–4 mo old) mice. They document changes in chemokine
receptor pattern with age that were not strain specific but that were
partially reversed by caloric restriction. Expression of chemokine
receptors characteristic of both naive and memory T cells increased
with age, suggesting that the observed changes in expression were not
due solely to the known shift from naive to memory phenotype during
aging. Similarly, expression of chemokine receptors associated with
both Th1 and Th2 cells increased with age, suggesting that the
age-associated shift in the Th1/Th2 profile cannot fully explain the
observed results. These findings may explain some of the underlying
mechanisms for the different clinical course observed in elderly
compared to younger individuals in diseases such as AIDS and rheumatoid
arthritis.
Signaling for dendritic cell maturation
Upon encountering a pathogen in peripheral
tissues, immature dendritic cells take up the
Ag, undergo maturation, and migrate to
lymph nodes to present the Ag to T cells. Dendritic cells express a
variety of receptors involved in the Ag uptake that initiates
maturation. Sedlik et al. (p. 846
) used complementation of
Rag-/- 
c-/- mice with
Syk-/- fetal liver cells to generate Syk-/-
bone marrow-derived dendritic cells. They show that the genetic
deletion of the tyrosine kinase Syk did not block differentiation of
immature dendritic cells from the bone marrow, or responses to LPS,
TNF-
, or CpG. However, Ag presentation and cell maturation induced
via FcR (receptors for immune complexes) were abrogated by deletion
of Syk. These findings indicate that proximal events in dendritic cell
signal transduction are different for different maturation stimuli.
Since the maturation state of dendritic cells appears to influence
whether the engagement of the T cell results in tolerance or an immune
response, these findings may shed light on the development of
autoimmunity.
Experience counts
It is well
established that a second encounter with a pathogen results in a more
rapid immune response than the initial encounter. However,
the mechanisms underlying the elevated secondary response of memory B
cells, compared to that of naive B cells during the primary response,
have not been fully elucidated. Tangye et al. (p. 686
) demonstrated
that human memory B cells have an increased intrinsic capacity to
proliferate and up-regulate CD38 in response to CD40 ligand, IL-2, and
IL-10, compared to naive B cells. Memory B cells entered cell division
earlier than naive B cells and a greater number of memory cells were
recruited into cell cycle, although the actual rate of proliferation of
both groups was similar. Both IgM-expressing and Ig isotype-switched
memory cells behaved similarly. Memory B cells that differentiated into
CD38+ cells following CD40 ligand stimulation proliferated
more rapidly than CD38- cells. The authors suggest that
these rapidly proliferating CD38+ cells may correspond to
plasmablasts observed in vivo.
Interfer(on)ing with proliferation
Type I IFNs, produced by a variety of cells
upon viral infection, are known to inhibit cell proliferation. This
presents a biological conundrum, since the host must mount an immune
response that involves T cell proliferation in order to eradicate the
viral infection. The paper by Dondi et al. (p. 749
) addresses the
regulation of T cell function by type I IFNs. While the entry of naive
resting cells into cycle following stimulation was delayed by IFN-,
no effect was observed on activated T cells. Activated T cells,
regardless of subset type, mounted a poor transcriptional response to
IFN- or IFN-
.The decline in the transcriptional
response to IFN occurred early after T cell activation, before cells
began to proliferate. However, the residual transcriptional response to
IFN- in activated T cells was sufficient to inhibit viral
replication in these cells. Therefore, the changes that occur in the
cell upon engagement of the TCR appear to alter the cell’s
responsiveness to type I IFNs.
CD40 ligand mRNA stability
CD40 ligand, a
TNF-family member expressed by Ag-activated
CD4+ T cells, plays a key role in the regulation of humoral
and cellular immune responses by engaging CD40 on B cells and
professional APC. The outcome of the response to CD40 ligand binding is
influenced by the duration of CD40 ligand expression. For example,
sustained expression favors differentiation of germinal center B cells
to memory B cells whereas transient expression promotes differentiation
of germinal center B cells to plasmacytoid B cells. The regulation of
CD40 ligand expression occurs at both transcriptional and
posttranscriptional levels. Kosinski et al. (p. 979
) examined factors
influencing the stability of CD40 ligand mRNA. They previously
demonstrated the binding of a protein complex, called Complex I, within
the pyrimidine rich sequence in the 3' untranslated region of CD40
ligand mRNA. They now show that binding of Complex I increased
the stability of the CD40 ligand transcript. Polypyrimidine
tract-binding protein was identified as a component, but not the sole
constituent, of Complex I. Two additional motifs in the 3' untranslated
region of CD40 ligand mRNA were shown to bind RNA-binding protein
complexes structurally related, but not identical to, Complex I.
Complement signaling in fibroblasts
Fibroblasts are key cells in the wound
repair process. During the inflammatory response to wounding,
activated complement components elicit intracellular signals upon
binding to fibroblasts. C1q is the initiator of the classical
complement cascade and consists of collagen-like tails and globular
heads. The C1q tail induces mitotic arrest in human fibroblasts.
Bordin and Whitfield (p. 667
) investigated the effect of C1q treatment
on the stress-activated mitogen-activated protein kinase (MAPK)
signaling pathway in fibroblasts. Increased
phosphorylation of components of the p38 MAPK pathway
occurred in response to C1q tails or the intact C1q molecule, but not
to C1q globular heads. Signaling through p38 MAPK was dependent, in
part, upon binding of C1q tails to the C1q receptor calreticulin and
correlated with the appearance of apoptotic nuclei in the cells.
Calreticulin is one of several possible receptors identified for C1q
and the findings reported here strengthen its candidacy as a functional
receptor. The authors conclude that p38 MAPK signaling is involved in
the mitotic arrest and apoptosis observed in fibroblasts
treated with C1q tails.
In vivo imaging
Airway
epithelial cells play a
role in acute inflammatory lung diseases such as asthma, cystic
fibrosis, pneumonia, and acute respiratory distress syndrome. The
transcription factor NF-
B is also involved in lung inflammation.
Sadikot et al. (p. 1091
) used a novel technique to study the
involvement of epithelial cell NF-B in lung inflammation. Using
adenoviral vectors, they transfected genes involved in NF-B
activation into lung epithelial cells of transgenic mice expressing the
luciferase gene under control of an NF-B-dependent promoter. This
technique allowed in vivo and in vitro measurement of NF-B
translocation via activation of the luciferase gene. The authors
showed that NF-B translocation and the subsequent activation
of pulmonary epithelial cells was responsible for neutrophilic
inflammation in the lungs. The type of in vivo imaging described in
this study provides a tool to better understand the complexity of whole
animal models for the study of human disease.
Aspirin is not for asthma
Lipid
mediators contribute to
the inflammatory response, and act rapidly to cause smooth muscle
contraction. Cyclooxygenase (COX) is an enzyme involved in the
synthesis of lipid mediators, specifically PGs, and exists in two
isoforms: COX-1 is often constitutively expressed whereas COX-2
expression is associated with inflammation. The regulation of COX
expression is cell-type specific. Pang et al. (p. 1043
) investigated
the regulation of COX-2 expression by nonsteroidal
anti-inflammatory drugs in human airway
smooth muscle cells and the part played by peroxisome
proliferator-activated receptors (PPARs) in this process. They showed
that COX-2 expression is induced by nonsteroidal anti-inflammatory
drugs, as well as by PGE2, the main PG produced by
human airway smooth muscle cells, and by the PPAR activator
15d-PGJ2. They also showed that PPAR is expressed in
human airway smooth muscle cells, and that a PPAR response
element in the COX-2 promoter is required for the induction of COX-2
expression by nonsteroidal anti-inflammatory drugs. Hence, despite
their inhibition of COX enzyme activity, nonsteroidal
anti-inflammatory drugs could paradoxically contribute to the
inflammatory state by inducing COX-2 expression, perhaps helping to
explain why nonsteroidal anti-inflammatory drugs are not effective
in the treatment of airway inflammation.
Related articles in The JI:
- Cyclooxygenase-2 Expression by Nonsteroidal Anti-inflammatory Drugs in Human Airway Smooth Muscle Cells: Role of Peroxisome Proliferator-Activated Receptors
- Linhua Pang, Mei Nie, Lisa Corbett, and Alan J. Knox
The JI 2003 170: 1043-1051.
[Abstract]
[Full Text]
- Selective IB Kinase Expression in Airway Epithelium Generates Neutrophilic Lung Inflammation
- Ruxana T. Sadikot, Wei Han, M. Brett Everhart, Ornella Zoia, R. Stokes Peebles, E. Duco Jansen, Fiona E. Yull, John W. Christman, and Timothy S. Blackwell
The JI 2003 170: 1091-1098.
[Abstract]
[Full Text]
- Cutting Edge: Proliferating Fibroblasts Respond to Collagenous C1q with Phosphorylation of p38 Mitogen-Activated Protein Kinase and Apoptotic Features
- Sandra Bordin and Douglas Whitfield
The JI 2003 170: 667-671.
[Abstract]
[Full Text]
- Intrinsic Differences in the Proliferation of Naive and Memory Human B Cells as a Mechanism for Enhanced Secondary Immune Responses
- Stuart G. Tangye, Danielle T. Avery, Elissa K. Deenick, and Philip D. Hodgkin
The JI 2003 170: 686-694.
[Abstract]
[Full Text]
- Down-Modulation of Responses to Type I IFN Upon T Cell Activation
- Elisabetta Dondi, Lars Rogge, Georges Lutfalla, Gilles Uzé, and Sandra Pellegrini
The JI 2003 170: 749-756.
[Abstract]
[Full Text]
- A Critical Role for Syk Protein Tyrosine Kinase in Fc Receptor-Mediated Antigen Presentation and Induction of Dendritic Cell Maturation
- Christine Sedlik, Daniel Orbach, Philippe Veron, Edina Schweighoffer, Francesco Colucci, Romina Gamberale, Andrea Ioan-Facsinay, Sjef Verbeek, Paola Ricciardi-Castagnoli, Christian Bonnerot, Victor L. J. Tybulewicz, James Di Santo, and Sebastian Amigorena
The JI 2003 170: 846-852.
[Abstract]
[Full Text]
- T Cell Chemokine Receptor Expression in Aging
- Ruran Mo, Jun Chen, Yin Han, Cecelia Bueno-Cannizares, David E. Misek, Pascal A. Lescure, Samir Hanash, and Raymond L. Yung
The JI 2003 170: 895-904.
[Abstract]
[Full Text]
- A Complex Containing Polypyrimidine Tract-Binding Protein Is Involved in Regulating the Stability of CD40 Ligand (CD154) mRNA
- Penelope A. Kosinski, Jennifer Laughlin, Karnail Singh, and Lori R. Covey
The JI 2003 170: 979-988.
[Abstract]
[Full Text]
