30 research outputs found
Lung dendritic cells and host immunity to infection
The lung is a portal of entry for numerous microbial pathogens, against
which evolution has created an adequate innate and adaptive immune
response. Dendritic cells (DCs) are central to the integration of innate
and specific immunity. These cells are located within the epithelium and
interstitium of the lung where they are influenced by the innate immune
system. Upon recognition and internalization of microbial antigens, DCs
migrate to the draining lymph nodes of the lung to initiate the specific
cellular and humoral immune response. By their capacity to integrate
stimuli derived from the pathogen, the host and the environment, they are
specialized to induce a protective immune response while at the same time
avoiding damage to the host. It is becoming increasingly clear that
dendritic cells are involved in the induction of immunity to viruses,
bacteria, mycobacteria and fungi. Some pathogens subvert the function of
dendritic cells to escape immune recognition. Not surprisingly, if
dendritic cell function fails, the consequence for the host is
immunodeficiency
Potential of immunoglobulin A to prevent allergic asthma
Allergic asthma is characterized by bronchial hyperresponsiveness, a defective barrier function, and eosinophilic lower airway inflammation in response to allergens. The inflammation is dominated by Th2 cells and IgE molecules and supplemented with Th17 cells in severe asthma. In contrast, in healthy individuals, allergen-specific IgA and IgG4 molecules are found but no IgE, and their T cells fail to proliferate in response to allergens, probably because of the development of regulatory processes that actively suppress responses to allergens. The presence of allergen-specific secretory IgA has drawn little attention so far, although a few epidemiological studies point at a reverse association between IgA levels and the incidence of allergic airway disease. This review highlights the latest literature on the role of mucosal IgA in protection against allergic airway disease, the mechanisms described to induce secretory IgA, and the role of (mucosal) dendritic cells in this process. Finally, we discuss how this information can be used to translate into the development of new therapies for allergic diseases based on, or supplemented with, IgA boosting strategies
Early IL-1 signaling promotes iBALT induction after influenza virus infection
Inducible bronchus-associated lymphoid tissue (iBALT) is a long lasting tertiary lymphoid tissue that can be induced following influenza A virus (IAV) infection. Previous studies have shown that iBALT structures containing germinal center (GC) B cells protect against repeated infection by contributing locally to the cellular and humoral immune response. If we are to exploit this in vaccination strategies, we need a better understanding on how iBALT structures are induced. One hypothesis is that the strength of the initial innate response dictates induction of iBALT. In the present study, we investigated the role of interleukin (IL)-1 and IL-1R signaling on iBALT formation. Mice lacking the IL-1R had a delayed viral clearance and, thus, a prolonged exposure to viral replication, leading to increased disease severity, compared to wild-type mice. Contradictorily, iBALT formation following clearance of the virus was heavily compromised in Il1r1-/- mice. Quantification of gene induction after IAV infection demonstrated induction of IL-1α and to a much lesser extent of IL-1β. Administration of recombinant IL-1α to the lungs of wild-type mice, early but not late, after IAV infection led to more pronounced iBALT formation and an increased amount of GC B cells in the lungs. Bone marrow chimeric mice identified the stromal compartment as the crucial IL-1 responsive cell for iBALT induction. Mechanistically, Q-PCR analysis of lung homogenates revealed a strongly diminished production of CXCL13, a B cell-attracting chemokine, in Il1r-/- mice during the early innate phase of IAV infection. These experiments demonstrate that appropriate innate IL-1α-IL-1R signaling is necessary for IAV clearance and at the same time instructs the formation of organized tertiary lymphoid tissues through induction of CXCL13 early after infection. These findings are discussed in the light of recent insights on the pathogenesis of tertiary lymphoid organ formation in the lung in various diseases where the IL-1 axis is hyperactive, such as rheumatoid arthritis and COPD
Prostaglandin D2 inhibits airway dendritic cell migration and function in steady state conditions by selective activation of the D prostanoid receptor 1
PGD(2) is the major mediator released by mast cells during allergic
responses, and it acts through two different receptors, the D prostanoid
receptor 1 (DP1) and DP2, also known as CRTH2. Recently, it has been shown
that PGD(2) inhibits the migration of epidermal Langerhans cells to the
skin draining lymph nodes (LNs) and affects the subsequent cutaneous
inflammatory reaction. However, the role of PGD(2) in the pulmonary immune
response remains unclear. Here, we show that the intratracheal
instillation of FITC-OVA together with PGD(2) inhibits the migration of
FITC(+) lung DC to draining LNs. This process is mimicked by the DP1
agonist BW245C, but not by the DP2 agonist DK-PGD(2). The ligation of DP1
inhibits the migration of FITC-OVA(+) DCs only temporarily, but still
inhibits the proliferation of adoptively transferred, OVA-specific,
CFSE-labeled, naive T cells in draining LNs. These T cells produced lower
amounts of the T cell cytokines IL-4, IL-10, and IFN-gamma compared with T
cells from mice that received FITC-OVA alone. Taken together, our data
suggest that the activation of DP receptor by PGD(2) may represent a
pathway to control airway DC migration and to limit the activation of T
cells in the LNs under steady state conditions, possibly contributing to
homeostasis in th
Airway eosinophils accumulate in the mediastinal lymph nodes but lack antigen-presenting potential for naive T cells
Asthma is characterized by infiltration of the airway wall with
eosinophils. Although eosinophils are considered to be effector cells,
recent studies have reported their ability to activate primed Th2 cells.
In this study, we investigated whether eosinophils are capable of
presenting Ag to unprimed T cells in draining lymph nodes (DLN) of the
lung and compared this capacity with professional dendritic cells (DC).
During development of eosinophilic airway inflammation in OVA-sensitized
and challenged mice, CCR3(+) eosinophils accumulated in the DLN. To study
their function, eosinophils were isolated from the bronchoalveolar lavage
fluid of mice by sorting on CCR3(+)B220(-)CD3(-)CD11c(dim) low
autofluorescent cells, avoiding contamination with other APCs, and were
intratracheally injected into mice that previously received CFSE-labeled
OVA TCR-transgenic T cells. Eosinophils did not induce divisions of T
cells in the DLN, whereas DC induced on average 3.7 divisions in 45.7% of
T cells. To circumvent the need for Ag processing or migration in vivo,
eosinophils were pulsed with OVA peptide and were still not able to induce
T cell priming in vitro, whereas DC induced vigorous proliferation. This
lack of Ag-presenting ability was explained by the very weak expression of
MHC class II on fresh eosinophils, despite expression of the costimulatory
molecules CD80 and ICAM-1. This investigation does not support any role
for airway eosinophils as APCs to naive T cells, despite their migration
to the DLN at times of allergen exposure. DC are clearly superior in
activating T cells in the DLN of the lung
Lipopolysaccharide-induced suppression of airway Th2 responses does not require IL-12 production by dendritic cells
The prevalence of atopic asthma, a Th2-dependent disease, is reaching
epidemic proportions partly due to improved hygiene in industrialized
countries. There is an inverse correlation between the level of
environmental endotoxin exposure and the prevalence of atopic
sensitization. As dendritic cells (DC) have been implicated in causing
sensitization to inhaled Ag, we studied the effect of endotoxin on Th2
development induced by bone marrow DC in vitro and by intratracheal
injection in vivo, with particular emphasis on the role played by the
polarizing cytokine IL-12. Bone marrow-derived DC stimulated with
Escherichia coli O26:B6 LPS produced IL-12p70 for a limited period of
time, after which production became refractory to further stimulation with
CD40 ligand, a phenomenon previously called "exhaustion." The level of
IL-12 production of DC did not correlate with Th1 development, as
exhausted OVA-pulsed DC were still capable of shifting the cytokine
pattern of responding OVA-specific Th cells toward Th1 in vitro and in
vivo. When mice were first immunized by intratracheal injection of OVA-DC
and subsequently challenged with OVA aerosol, prior in vitro stimulation
of DC with LPS reduced the development of airway eosinophilia and Th2
cytokine production. Most surprisingly, the capacity of LPS to reduce
Th2-dependent eosinophilic airway inflammation was IL-12-independent
altogether, as IL-12p40 knockout DC had a similar reduced capacity to
prime for Th2 responses. These results suggest that LPS reduces
sensitization to inhaled Ag by reducing DC-driven Th2 development, but
that IL-12 is not necessary for this effect
The potential of radiotherapy to enhance the efficacy of renal cell carcinoma therapy
Renal cell carcinoma (RCC) is an immunogenic tumor, but uses several immune-suppressive mechanisms to shift the balance from tumor immune response toward tumor growth. Although RCC has traditionally been considered to be radiation resistant, recent evidence suggests that hypofractionated radiotherapy contributes to systemic antitumor immunity. Because the efficacy of antitumor immune responses depends on the complex balance between diverse immune cells and progressing tumor cells, radiotherapy alone is unlikely to induce persistent antitumor immunity. Therefore, the combination of radiotherapy with drugs having synergistic immunomodulatory properties holds great promise with the optimal timing and sequence of modalities depending on the agent used. We highlight the immunomodulatory properties of targeted therapies, such as tyrosine kinase inhibitors, mammalian target of rapamycin (mTOR) inhibitors and vascular endothelial growth factor (VEGF) neutralizing antibodies, and will suggest a combination schedule with radiotherapy based on the available literature. We also address the combination of radiotherapy with innovative treatments in the field of immunotherapy
Proinflammatory bacterial peptidoglycan as a cofactor for the development of central nervous system autoimmune disease
Upon stimulation by microbial products through TLR, dendritic cells (DC) acquire the capacity to prime naive T cells and to initiate a proinflammatory immune response. Recently, we have shown that APC within the CNS of multiple sclerosis (MS) patients contain peptidoglycan (PGN), a major cell wall component of Gram-positive bacteria, which signals through TLR and NOD. In this study, we report that Staphylococcus aureus PGN as a single component can support the induction of experimental autoimmune encephalomyelitis (EAE) in mice, an animal model for MS. Mice immunized with an encephalitogenic myelin oligodendrocyte glycoprotein peptide in IFA did not develop EAE. In contrast, addition of PGN to the emulsion was sufficient for priming of autoreactive Th1 cells and development of EAE.
In vitro studies demonstrate that PGN stimulates DC-mediated processes,
reflected by increased Ag uptake, DC maturation, Th1 cell expansion,
activation, and proinflammatory cytokine production. These data indicate
that PGN-mediated interactions result in proinflammatory stimulation of
Ag-specific effector functions, which are important in the development of
EAE. These PGN-mediated processes may occur both within the peripheral
ly
Alveolar macrophages develop from fetal monocytes that differentiate into long-lived cells in the first week of life via GM-CSF
Tissue-resident macrophages can develop from circulating adult monocytes or from primitive yolk sac-derived macrophages. The precise ontogeny of alveolar macrophages (AMFs) is unknown. By performing BrdU labeling and parabiosis experiments in adult mice, we found that circulating monocytes contributed minimally to the steady-state AMF pool. Mature AMFs were undetectable before birth and only fully colonized the alveolar space by 3 d after birth. Before birth, F4/80hiCD11blo primitive macrophages and Ly6ChiCD11bhi fetal monocytes sequentially colonized the developing lung around E12.5 and E16.5, respectively. The first signs of AMF differentiation appeared around the saccular stage of lung development (E18.5). Adoptive transfer identified fetal monocytes, and not primitive macrophages, as the main precursors of AMFs. Fetal monocytes transferred to the lung of neonatal mice acquired an AMF phenotype via defined developmental stages over the course of one week, and persisted for at least three months. Early AMF commitment from fetal monocytes was absent in GM-CSF-deficient mice, whereas short-term perinatal intrapulmonary GM-CSF therapy rescued