Cells In Allergic Inflammation Research Articles

Characterization of the promoter of human CRTh2, a prostaglandin D 2 receptor

Chemoattractant-receptor homologous molecule expressed on Th2 cells (CRTh2) is a receptor for prostaglandin (PG)D 2, a lipid mediator involved in allergic inflammation. CRTh2 is expressed by Th2 cells, eosinophils and basophils and PDG 2–CRTh2 signaling induces calcium mobilization, cell migration and expression of the Th2 cytokines IL-4, IL-5, and IL-13. Despite the role of CRTh2 in allergic inflammation, transcriptional regulation of this gene has not been studied. Here, we demonstrated that a reporter construct of the CRTh2 promoter was induced following T cell stimulation. This activity could be further enhanced by over-expression of GATA-3, but not NFAT2 or STAT6. Electromobility shift assay demonstrated GATA-3 binding to a probe from the CRTh2 promoter. This study provides the first detailed analysis of transcriptional regulation of the human CRTh2 promoter. These findings may help identify strategies to attenuate expression of this gene and influence the maintenance and proliferation of Th2 cells in allergic inflammation.

Airway remodeling and RELM-β

type 2 inflammatory responses are characterized by differentiated CD4+ T helper type 2 (Th2) cells that secrete a panel of cytokines including IL-4, IL-5, IL-9, and IL-13 with the recruitment of multiple effector cells, including B cells producing IgE, mast cells, eosinophils, and basophils.

The effect of Bacillus Calmette-Guerin in a mouse model of allergic rhinitis

To develop an allergic rhinitis model via local sensitization of mice with Dermatophagoides pteronyssinus and to use the model to investigate the antiallergic effect of Bacillus Calmette-Guerin (BCG). BALB/c mice were randomized to the allergic rhinitis group, the BCG group sensitized with D pteronyssinus via local sensitization for 7 weeks, or the control group. The BCG group received 1 x 10(5) colony-forming unit/mL of BCG seven times. We evaluated symptoms, nasal mucosa eosinophilia, serum total IgE, cytokines, and eosinophilia in bronchoalveolar lavage fluid. In the allergic rhinitis group, allergy symptoms (P < 0.001), eosinophil count (P < 0.001), total IgE (P < 0.001), inflammatory cells (P < 0.01), and IL-13 (P = 0.046) increased and interferon gamma (IFN-gamma) (P < 0.001) decreased compared with the control group. In the BCG group, allergy symptoms (P < 0.001), eosinophil count (P < 0.001), and inflammatory cells (P < 0.01) decreased and IFN-gamma (P = 0.031) increased compared with the allergic rhinitis group. In an allergic rhinitis animal model developed via local sensitization of mice with D pteronyssinus, BCG was shown to exhibit an antiallergic effect.

Roles of dendritic cells in allergic inflammation: A new therapeutic target for bronchial asthma

Roles of dendritic cells in allergic inflammation: A new therapeutic target for bronchial asthma

Proteomic Identification of In Vivo Substrates for Matrix Metalloproteinases 2 and 9 Reveals a Mechanism for Resolution of Inflammation

Clearance of allergic inflammatory cells from the lung through matrix metalloproteinases (MMPs) is necessary to prevent lethal asphyxiation, but mechanistic insight into this essential homeostatic process is lacking. In this study, we have used a proteomics approach to determine how MMPs promote egression of lung inflammatory cells through the airway. MMP2- and MMP9-dependent cleavage of individual Th2 chemokines modulated their chemotactic activity; however, the net effect of complementing bronchoalveolar lavage fluid of allergen-challenged MMP2(-/-)/MMP9(-/-) mice with active MMP2 and MMP9 was to markedly enhance its overall chemotactic activity. In the bronchoalveolar fluid of MMP2(-/-)/MMP9(-/-) allergic mice, we identified several chemotactic molecules that possessed putative MMP2 and MMP9 cleavage sites and were present as higher molecular mass species. In vitro cleavage assays and mass spectroscopy confirmed that three of the identified proteins, Ym1, S100A8, and S100A9, were substrates of MMP2, MMP9, or both. Function-blocking Abs to S100 proteins significantly altered allergic inflammatory cell migration into the alveolar space. Thus, an important effect of MMPs is to differentially modify chemotactic bioactivity through proteolytic processing of proteins present in the airway. These findings provide a molecular mechanism to explain the enhanced clearance of lung inflammatory cells through the airway and reveal a novel approach to target new therapies for asthma.

Adenosine A 1 receptor antagonist versus montelukast on airway reactivity and inflammation

Adenosine produces bronchoconstriction in allergic rabbits, primates, and humans by activating adenosine A 1 receptors. Previously, it is reported that a high dose of L-97-1, a water-soluble, small molecule adenosine A 1 receptor antagonist, blocks early and late allergic responses, and bronchial hyper-responsiveness to histamine in a hyper-responsive rabbit model of allergic asthma. Effects of a lower dose of L-97-1 are compared to montelukast, a cysteinyl leukotriene-1 receptor antagonist on early allergic response, late allergic response, bronchial hyper-responsiveness, and inflammatory cells in bronchoalveolar lavage (BAL) fluid following house dust mite administration. Rabbits received intraperitoneal injections of house dust mite extract within 24 h of birth followed by booster house dust mite injections. Hyper-responsive rabbits received aerosolized house dust mite (2500 allergen units), 1 h after intragastric administration of L-97-1 (1 mg/kg) or montelukast (0.15 mg/kg) and lung dynamic compliance was measured for 6 h. Lung dynamic compliance was significantly higher following L-97-1 at all time points and with montelukast at 60–300 min following house dust mite ( P < 0.05). L-97-1 blocks both early and late allergic responses. Montelukast blocks only the late allergic response. Both L-97-1 and montelukast significantly blocked bronchial hyper-responsiveness at 24 h ( P < 0.05). Both L-97-1 and montelukast significantly reduced BAL eosinophils at 6 h and neutrophils at 6 and 24 h ( P < 0.05). L-97-1 significantly reduced BAL lymphocytes at 6 and 24 h ( P < 0.05). Montelukast significantly reduced BAL macrophages at 6 and 24 h ( P < 0.05). By blocking both bronchoconstriction and airway inflammation, L-97-1 may be an effective oral anti-asthma treatment.

Differential expression of chitinases identify subsets of murine airway epithelial cells in allergic inflammation

The mammalian chitinase family includes members both with and without enzymatic activity against chitin, a product of fungal cell walls, exoskeletons of crustaceans and insects, and the microfilarial sheaths of parasitic nematodes. Two members of that family, Ym1 and acidic mammalian chitinase (AMCase), are strongly upregulated in pulmonary T helper (Th) 2 inflammation but not in Th1 inflammation. The sites of expression of these products are incompletely known. We show here that, in two different models of Th2 inflammation, Ym1 and AMCase are mutually exclusively expressed in proximal vs. distal airway epithelium, respectively, whereas both are expressed in alveolar macrophages. This regional difference along the airway corresponds to the previously noted distinction between mucus positive proximal cells and mucus negative distal cells under the same conditions. Among distal cells, AMCase colocalizes with epithelial cells expressing the Clara cell marker Clara cell secretory protein. These AMCase-expressing cells retain expression of FOXA2, a transcription factor whose downregulation in association with IL-13 signaling has previously been associated with production of mucus in proximal airway epithelial cells. These results provide evidence that secretory cells of proximal and distal airways undergo fundamentally different gene expression programs in response to allergic inflammation. Furthermore, AMCase provides the first positive molecular marker of distal Clara cell secretory protein-expressing cells under these conditions.

Toll-like receptor agonists differentially regulate cysteinyl-leukotriene receptor 1 expression and function in human dendritic cells

Dendritic cells (DCs) acquire, during their maturation, the expression of the chemokine receptor CCR7 and the ability to migrate to lymph nodes in response to CC chemokine ligand 19 (CCL19). This migration is impaired in mice lacking the leukotriene (LT) C4 transporter and restored by addition of exogenous LTC4. To define the role of LT in human DC function, we studied the expression and function of the cysteinyl-leukotriene (CysLT) receptors during DC differentiation from monocytes and subsequent maturation. Receptor expression was measured by flow cytometry and real-time PCR. Responsiveness to LTD4 stimulation was assessed by calcium flux and chemotaxis. Maturation of DC with LPS, a classic Toll-like receptor 4 agonist, reduced CysLT receptor 1 (CysLT1) expression by 50%, whereas CysLT receptor 2 expression was increased. In contrast, the Toll-like receptor 3 agonist poly inosinic and cytidylic acid (polyI:C) had no effect on receptor expression. Downregulation of CysLT1 expression by LPS could not be mimicked by TNF-alpha alone or in combination with IL-1beta or IL-6. It was, however, prevented by inhibitors of COX and could be reproduced by a combination of TNF-alpha and prostaglandin E2. Immature DCs and DCs matured with polyI:C, but not with LPS, responded to LTD4 with a robust cytosolic calcium flux, which was prevented by the CysLT1 antagonist montelukast. LTD4 induced DC chemotaxis and enhanced DC migration in response to CCL19 in DCs matured with polyI:C, but only weakly in DCs matured with LPS. Our data suggest that human DCs may differentially respond to leukotriene, depending on their maturational stimuli. Our study demonstrates that some microbial agents can reduce the migration of dendritic cells in response to leukotrienes, with potential for differential involvement of these cells in allergic inflammation.

Eosinophilia in the upper gastrointestinal tract is not a characteristic feature in cow’s milk sensitive gastro–oesophageal reflux disease. Measurement by two methodologies

Background: An association between cow’s milk hypersensitivity (CMH) and gastro–oesophageal reflux disease (GERD) in childhood has been reported in the past decade. Aim: To assess whether biopsies from the upper...

TGF-beta1, IL-1beta, and Th2 cytokines stimulate vascular endothelial growth factor production from conjunctival fibroblasts

Giant papillary formation containing newly formed vessels is a major characteristic of severe allergic conjunctivitis, such as atopic keratoconjunctivitis (AKC) or vernal keratoconjunctivitis (VKC). We examined production of vascular endothelial growth factor (VEGF) from cultured conjunctival fibroblasts from normal volunteers under stimulation with type 1-, type 2-helper T cell derived and proinflammatory cytokines to investigate the mechanism of giant papillae formation in AKC/VKC. Primary cultured conjunctival fibroblasts were incubated with interleukin (IL)-4, IL-13, IL-1beta, IL-2, tumor necrotizing factor (TNF)-alpha, interferon (IFN)-gamma, or transforming growth factor (TGF)-beta1. Effects of cytokines on VEGF protein secretion in supernatant were assessed by ELISA, and VEGF mRNA expression in cultured cells were assessed by quantitative PCR. TGF-beta1 most effectively increased VEGF concentration with dose- and time-dependent manner IL-1beta, IL-4, and IL-13 significantly increased VEGF concentration. Though IL-2 also showed slight increase of VEGF concentration, it was not statistically significant. TNF-alpha and INF-gamma did not increase VEGF concentration. Quantitative PCR showed significant increase of VEGF mRNA in TGF-beta1, IL-1beta, and IL-4 stimulated fibroblasts. TGF-beta1, IL-1beta, and Th2 cytokines from allergic inflammatory cells induced VEGF production in conjunctival fibroblasts, and may play a crucial role in neovascularization and formation of giant papillae in AKC/VKC.

Urinary tract diseases revealed after DTP vaccination in infants and young children: cytokine irregularities and down-regulation of cytochrome P-450 enzymes induced by the vaccine may uncover latent diseases in genetically predisposed subjects.

Prophylactic vaccinations may sometimes shorten the incubation period of some illnesses and/or convert a latent infection/inflammation into a clinically apparent disease. Cytokines play a major role in mediating the inflammatory process in various clinical entities and represent a potential source of tissue damage if their production is not sufficiently well controlled. It seems that irregularities in production of proinflammatory cytokines may be responsible for the abnormalities associated with full-blown clinical symptoms of various urinary tract diseases observed after DTP vaccination in 13 infants and young children hospitalized over the past 24 years. On admission, upper respiratory tract diseases, atopic dermatitis, and/or latent urinary tract infection/inflammation were found in these children. It is suggested that the whole-cell pertussis present in DTP vaccine, acting as an excessive stimulus in these patients, produced symptoms reminiscent of biologic responses to circulating proinflammatory monokines such as IL-1beta, TNF-alpha, and IL-6 because earlier it was reported that in vitro the whole-cell vaccine induced significantly more such cytokine production than did the acellular pertussis or diphtheria-tetanus-only vaccine. Analysis of the cellular immune disturbances previously reported in urinary tract infection/inflammation (increased serum and/or urinary IL-1alpha, IL-1 receptor antagonist, IL-6 and IL-8), steroid-sensitive nephrotic syndrome (increased IL-2, IFN-gamma, TNF-alpha, and decreased or increased IL-4, depending on the cells studied), and atopic dermatitis (decreased IFN-gamma and increased IL-4 production), may suggest that similar subclinical chronic cytokine-mediated abnormalities produced in the course of latent diseases revealed in our patients, combined with those caused by DTP vaccination stimulus, were responsible for the pathomechanism of these clinical entities. This speculation is in agreement with the reports on the long-lasting induction of cytokine release and down-regulation of hepatic cytochrome P-450 isoenzyme activities after administration of DTP vaccine to mice and may be supported by the fact that TH1 phenotype is associated with the up-regulation of intercellular adhesion molecule-1 and RANTES, whereas TH2 phenotype is associated with the up-regulation of the vascular cell adhesion molecule and P-selectin, which are key players in the migration into inflamed tissues and localization of lymphocytes and other allergic effector and inflammatory cells. Because several inflammatory cytokines down-regulate gene expression of major cytochrome P-450 and/or other enzymes with the specific effects on mRNA levels, protein expression, and enzyme activity, thus affecting the metabolism of several endogenous lipophilic substances such as steroids, lipid-soluble vitamins, prostaglandins, leukotrienes, thromboxanes, and exogenous substances, their irregularities in the body may eventually lead to the flare of latent diseases in some predisposed subjects. Also, interleukin genetic polymorphisms, especially the constellation of TNF-alpha and IL-6 genetic variants, might predispose some infants with infection to a more than usually intense inflammatory response in the kidneys after vaccination. It seems that the aforementioned pathomechanism may also be responsible for some cases of sudden infant death syndrome, which is often preceded by infection/inflammation.

Allergic rhinitis in children: association with asthma

SummaryThe incidence of allergic rhinitis in paediatric bronchial asthma patients was about 80% according to a questionnaire survey. Watery nasal discharge and nose rubbing were common symptoms of paediatric allergic rhinitis, while nasal congestion and sneezing increased with age. Although there were slight differences depending on the age of patients, one‐third to nearly half were believed to have nasal symptoms and asthma attacks. The first wheezing episode preceded nasal symptoms in the majority of patients, but onset of allergic rhinitis occurred &gt; 1 year before asthma in a little over 10%. The age of onset of allergic rhinitis was 1 year in these patients, which was clearly earlier than that observed in patients who first developed asthma (4 years). Furthermore, the incidence of cedar pollinosis was higher in patients who developed allergic rhinitis first than in those who developed asthma first, suggesting that asthma patients who develop allergic rhinitis first exhibit pronounced nasal hypersensitivity. Allergic inflammatory cells are present in the nasal mucosa of asthma patients who do not exhibit distinct allergic rhinitis symptoms, so nasal sensitization does not necessarily lead to allergic rhinitis symptoms, suggesting the existence of some other factor that induces nasal hypersensitivity. On nasal smear, the appearance of mast cells preceded a positive radioallergosorbent test (RAST), and the appearance of eosinophils and basophils was consistent with the degree of sensitization. Anti‐allergic agents appear efficacious in patients' mast cells positive on nasal smear cytology with negative house dust mite RAST, suggesting that nasal smear cytology may be useful when beginning medication.

Overlapping and independent contributions of MMP2 and MMP9 to lung allergic inflammatory cell egression through decreased CC chemokines.

The mechanisms that initiate allergic lung inflammation are relevant to expression of diseases such as asthma, but the factors underlying resolution of inflammation are equally important. Previously, we demonstrated the importance of matrix metalloproteinase 2 (MMP2) for airway egression of lung eosinophils, a critical anti-inflammatory mechanism without which mice are rendered highly susceptible to lethal asphyxiation. Here we show that leukocyte MMP9 is the dominant airway MMP controlling inflammatory cell egression. The allergic lung phenotype of MMP9-/- mice was similar to WT and was not altered by concomitant deletion of the MMP2 gene (double knockout; dko). However, inflammatory cells accumulated aberrantly in the lungs of allergen-challenged MMP9-/- and dko mice and fewer eosinophils and neutrophils were present in bronchoalveolar lavage. These aberrant cellular trafficking patterns were explained by disruption of transepithelial chemokine gradients, in MMP2-/- mice affecting only eotaxin (CCL11), but in MMP9-/- and dko mice involving eotaxin, MARC (CCL7), and TARC (CCL17). Thus, by establishing multiple transepithelial chemokine gradients, MMP9 is broadly implicated in the resolution of allergic inflammation, an essential protective mechanism that overlaps with a more limited role played by MMP2.

Localization and enhanced mRNA expression of the orphan chemokine receptor L-CCR in the lung in a murine model of ovalbumin-induced airway inflammation.

Various CC chemokine receptors are expressed on effector cells in allergic inflammation and their distinct expression pattern may dictate, to a large extent, the migration of inflammatory cells to sites of airway inflammation. The lipopolysaccharide (LPS)-inducible CC chemokine receptor (L-CCR) is an orphan chemokine receptor that has previously been identified in the murine macrophage cell line RAW 264.7 and in murine brain glial cells. In this study we investigated the induction and localization of L-CCR mRNA expression in mouse lung after ovalbumin (OVA)-induced airway inflammation. Both RT-PCR experiments and in situ hybridization (ISH) experiments in whole lung sections revealed a rapid upregulation of L-CCR mRNA expression as early as 1 hr and 3 hr after OVA challenge. Expression was found predominantly in MAC3(+) macrophages and in bronchial epithelium, as shown by ISH and immunohistochemistry (IHC). We demonstrated that L-CCR mRNA expression is strongly upregulated in mouse lung after OVA challenge and is localized in macrophages and bronchial epithelium. Regarding the likely role of L-CCR as a chemokine receptor with the putative ligand monocyte chemotactic protein-1 (MCP-1, CCL2), this receptor may have an important function in the early phase of airway inflammation.

Inhibitory Effect of Water‐Soluble Chitosan on TNF‐α and IL‐8 Secretion from HMC‐1 Cells

Mast cells are known to play an active role as effector cells in allergic inflammation and in diverse immunological and pathological processes. Activated mast cell‐derived pro‐inflammatory cytokines are important pathologic factors of progression of allergic inflammation. In this study, we investigated whether pro‐inflammatory cytokines (TNF‐α and IL‐8) can be induced by calcium stimulation in HMC‐1 cells, and high molecular weight water‐soluble chitosan (WSC) can inhibit the production of these cytokines. We provided evidence that the secretion of TNF‐α and IL‐8 from HMC‐1 cells was induced by Ca2 +‐ionophore A23187 or Ca2 +‐ATPase inhibitor TSG. Treatment of WSC (10 µg/ml) prior to stimulation with calcium agonists significantly blocked the secretion of TNF‐α by 65.1% for A23187 and 87.7% for TSG. IL‐8 secretion in response to A23187 or TSG was inhibited by 49.2% for A23187 and 34.1% for TSG, respectively, compared to absence of WSC. These results suggest that WSC has potential regulatory effects on allergic inflammatory diseases by down‐modulating Ca2 +‐induced mast cell activation.

Fibrosis in ocular allergic inflammation: recent concepts in the pathogenesis of ocular allergy.

Mast cells and eosinophils are the main effector cells in allergic inflammation, but there is now compelling evidence that fibroblasts are also important players in the inflammatory response. In fact, they respond to different stimuli and release several mediators that modulate mast-cell and eosinophil functionality. In several allergic conditions such as vernal keratoconjunctivitis, asthma and atopic dermatitis the chronic presence of the inflammatory process has been associated with fibrosis and tissue remodeling, which in turn could cause irreversible alterations in the organ anatomy and functions. This review will discuss current advances in mast cell, eosinophil and fibroblast interactions in terms of their importance in the perpetuation of allergic inflammation and in contributing to the fibrosis and/or remodeling process in ocular allergy. As a main example of allergic ocular diseases associated with fibrosis, vernal keratoconjunctivitis is discussed in the light of recent findings. Several studies have recently shown that fibroblasts can modulate the functions of mast cells and eosinophils through the membrane form of stem cell factor and granulocyte-macrophage colony-stimulating factor, respectively. On the other hand, fibroblasts can be affected by inflammatory mediators derived from mast cells and eosinophils, such as transforming growth factor beta and nerve growth factor and by the T helper type 2 cytokines, IL-4 and IL-13, and vernal keratoconjunctivitis-derived fibroblasts display altered functions. Considerable useful information has been gained about the role of mast cells, eosinophils and fibroblasts in the perpetuation of allergic inflammation and tissue fibrosis and/or remodeling in general, and specifically in ocular allergy.

Allergen-induced fluctuation in CC chemokine receptor 3 expression on bone marrow CD34+ cells from asthmatic subjects: significance for mobilization of haemopoietic progenitor cells in allergic inflammation.

There is increasing evidence that primitive progenitors migrate from the bone marrow (BM) via the peripheral circulation to tissue sites where they undergo in situ differentiation to provide a continued source of effector cells, such as eosinophils, during an allergic inflammatory response. To study mechanisms of progenitor cell mobilization in allergic reactions, we investigated fluctuations in the expression of the eotaxin receptor, CC chemokine receptor 3 (CCR3), on CD34+ cells from stable asthmatics following allergen (i.e. antigen) challenge. BM aspirates were taken from seven early responder (ER) and 10 dual responder (DR) asthmatics who, following antigen challenge developed only an early bronchoconstrictor response and an early and late- bronchoconstrictor response, respectively. Expression of CCR3 was detected on primitive (CD34+ cells) and eosinophil-lineage committed progenitors (CD34+ interleukin-5 receptor alpha-subunit+ cells) by flow cytometry and confirmed by co-localization of CCR3 messenger RNA to CD34 immunopositive cells using in situ hybridization. When preantigen levels were compared to 24-hr postantigen levels, significant increases in BM CD34+ CCR3+ cells were detected in DR, who also developed a significant sputum and blood eosinophilia and increased methacholine airway responsiveness. In contrast, a significant attenuation of BM CD34+ CCR3+ cells was observed in ER. In a dose-dependent manner eotaxin, but not interleukin (IL)-5, stimulated CD34+ progenitor cell migration in vitro. This migrational response to eotaxin was abrogated by anti-CCR3 monoclonal antibody and primed by preincubation with IL-5. We propose that fluctuations in CCR3 expression on human BM CD34+ cells may facilitate chemokine-mediated progenitor cell mobilization to the peripheral circulation and the resultant development of pulmonary eosinophilia, a cardinal feature of asthma.

A mechanism of antigen-induced goblet cell degranulation in the nasal epithelium of sensitized rats

Background: We have produced hypertrophic and metaplastic changes of goblet cells in nasal epithelium of ovalbumin (OVA)-sensitized rats by intranasal challenge with OVA. A variety of allergic mediators and inflammatory cells are capable of stimulating goblet cell degranulation (epithelial mucus secretion); however, little is known about the mechanism by which antigen induces mucus hypersecretion. Objective: Our aim was to explain the mechanism of goblet cell degranulation in allergic inflammation. Methods: Antigen-induced goblet cell degranulation was evaluated by the transient decrease of epithelial mucosubstance 1 to 6 hours after intranasal challenge with OVA in nasal epithelium of OVA-sensitized rats. The effects of the H1-antagonist (d -chlorpheniramine malate), H2-antagonist (cimetidine), atropine, indomethacin, cysteinyl leukotriene (cysLT) antagonist (ONO1078), and antirat PMN antiserum on OVA-induced goblet cell degranulation were examined. Results: Goblet cell secretion 1 hour after OVA challenge was significantly inhibited by H1-antagonist, atropine, and cysLT antagonist, whereas the secretion 6 hours after the challenge was significantly inhibited by cysLT antagonist and antirat PMN antiserum. Circulating PMN cells and mucosal infiltrating eosinophils were completely abolished by antirat PMN antiserum. Conclusions: These results indicate the different mechanisms of goblet cell secretion between early-phase (1 hour after OVA challenge) and late-phase (6 hours after the challenge) reactions. Histamine stimulates early-phase secretion through the H1-receptor of cholinergic nerve terminals, and infiltrating inflammatory cells (eosinophils and/or neutrophils) play a role in late-phase secretion. CysLTs (leukotrienes C4, D4, and E4) are important for both early-phase and late-phase secretion. (J Allergy Clin Immunol 2003;112:119-25.)

CD44--a sticky target for asthma.

CD44--a sticky target for asthma.

Human dendritic cells activated by TSLP and CD40L induce proallergic cytotoxic T cells.

Human thymic stromal lymphopoietin (TSLP) is a novel epithelial cell–derived cytokine, which induces dendritic cell (DC)-mediated CD4+ T cell responses with a proallergic phenotype. Although the participation of CD8+ T cells in allergic inflammation is well documented, their functional properties as well as the pathways leading to their generation remain poorly understood. Here, we show that TSLP-activated CD11c+ DCs potently activate and expand naive CD8+ T cells, and induce their differentiation into interleukin (IL)-5 and IL-13–producing effectors exhibiting poor cytolytic activity. Additional CD40L triggering of TSLP-activated DCs induced CD8+ T cells with potent cytolytic activity, producing large amounts of interferon (IFN)-γ, while retaining their capacity to produce IL-5 and IL-13. These data further support the role of TSLP as initial trigger of allergic T cell responses and suggest that CD40L-expressing cells may act in combination with TSLP to amplify and sustain pro-allergic responses and cause tissue damage by promoting the generation of IFN-γ–producing cytotoxic effectors.