Role of thymic stromal lymphopoietin in the pathogenesis of nasal polyposis

IntroductionPolyposis is an end form of chronic mucosal inflammation in a number of disorders and has an important impact on patient’s life quality. Thymic stromal lymphopoietin (TSLP) is involved in many inflammatory processes such as asthma and allergic rhinitis (AR). The aim of this study is to elucidate the role of TSLP in the pathogenesis of polyposis.MethodsNinety-four patients with nasal polyposis (NP) and/or allergic rhinitis (AR) were treated with inferior turbinectomy and polyp resection. Levels of TSLP in the nasal epithelial layer were measured; expression of TSLP receptor and OX40 ligand (OX40L) was assessed in isolated nasal mucosal dendritic cells (DC); tumor necrosis factor (TNF), interleukin (IL)-4 and interferon (IFN)-γ expressions were determined in isolated nasal mucosal CD4⁺ T cells.ResultsThe levels of TSLP in nasal epithelial layer were higher in the NP group than in the non-NP group. Higher expression of TSLP receptor and OX40L were detected in DCs of NP nasal mucosa. TNF-α⁺ IL-4⁺CD4⁺ T cells were detected in NP/AR nasal mucosa; TNF⁺ IFN-γ⁺ CD4⁺ T cells were identified in NP/non-AR nasal mucosa. TSLP-primed DCs drove naive CD4⁺ T cells to become TNF⁺ IL-4⁺ CD4⁺ T cells, whereas TSLP/lipopolysaccharide-primed DCs induced naive CD4⁺ T cells to become TNF⁺ IFN-γ⁺ T cells.ConclusionsThe data indicate that TSLP is involved in the pathogenesis of polyposis.     

Thymic stromal lymphopoietin: A potential therapeutic target for allergy and asthma

Thymic stromal lymphopoietin (TSLP) is an interleukin (IL)-7-like cytokine that has recently been implicated as central to the microenvironment and is permissive for the immunologic cascade that initiates and propagates allergic immune responses. In humans, TSLP is produced predominantly by epithelial cells and activated mast cells, and stimulates myeloid dendritic cells (mDC), which uniquely express the heterodimeric TSLP receptor. TSLP-activated mDC can promote naïve CD4+ T cells to differentiate into a Th2 phenotype and can promote the expansion of CD4+ Th2 memory cells. Recent evidence implicates TSLP as playing a pivotal role in the pathobiology of allergic asthma and atopic dermatitis. The potential for TSLP to provide a new therapeutic target for the treatment of allergic disorders is compelling, and elucidating the mechanisms that regulate TSLP expression and the effects of TSLP on orchestrating the immune response toward a Th2 phenotype should facilitate this quest.     

TSLP acts on infiltrating effector T cells to drive allergic skin inflammation

Thymic stromal lymphopoietin (TSLP) is a cytokine expressed by epithelial cells, including keratinocytes, and is important in allergic inflammation. Allergic skin inflammation elicited by epicutaneous immunization of mice with ovalbumin (OVA), a potential model of atopic dermatitis, was severely impaired in TSLPR^−/− mice, as evidenced by decreased infiltration of eosinophils and decreased local expression of T helper 2 (Th2) cytokines. However, secretion of Th2 cytokines by splenocytes from epicutaneous sensitized TSLPR^−/− mice in response to OVA was normal. Skin dendritic cells from TSLPR^−/− mice were normal in their ability to migrate to draining lymph nodes, express activation markers, and induce proliferation and Th2 cytokine production by naïve T cells. CD4⁺ T cells from TSLPR^−/− mice expressed the skin homing receptor E-selectin ligand normally, and homed to the skin normally, but failed to transfer allergic skin inflammation to WT recipients. TSLP enhanced Th2 cytokine secretion in vitro by targeting TSLPR on antigen specific T cells. Intradermal injection of anti-TSLP blocked the development of allergic skin inflammation after cutaneous antigen challenge of OVA immunized WT mice. These findings suggest that TSLP is essential for antigen driven Th2 cytokine secretion by skin infiltrating effector T cells and could be a therapeutic target in allergic skin inflammation.     

IL-33 Promotes the Induction and Maintenance of Th2 Immune Responses by Enhancing the Function of OX40 Ligand

Background: In Th2 immune responses, TSLP is a key player by induction of OX40-ligand (OX40L) on dendritic cells (DCs), which is the trigger to induce Th2 cell-mediated allergic cascade. Thus, TSLP-DC-OX40L axis might be the principal pathway in the inflammatory cascades in atopic dermatitis and asthma. IL-33, which is produced by epithelial cells, has been implicated in the Th2 immune responses and pathogenesis of the allergic disorders. However, the role of IL-33 in the Th2-polarizing TSLP-DC-OX40L axis still remains largely elusive. We focused on the ability of IL-33 to promote OX40L-mediated Th2 responses.Methods: Purified human naïve or memory CD4 + T cells were stimulated with recombinant OX40L or TSLP- treated DCs (TSLP-DCs) in the presence of IL-33, and the cytokine production by the primed T cells was examined. We also performed immunohistochemical analyses for the expression of IL-33 in specimens of lymph node and skin from the patients with atopic dermatitis.Results: IL-33 remarkably enhanced TSLP-DCs-driven or OX40L-driven Th2 responses from naïve T cells and the Th2 functional attributes of CRTH2 + CD4 + Th2 memory cells by the increased production of IL-5, IL-9, and IL-13. In addition, IL-33 was expressed in the nuclei of epithelial cells in not only skin lesion but also lymph nodes of the patient with atopic dermatitis, suggesting a specialized role in adaptive T cell-priming phase.Conclusions: IL-33 works as a positive regulator of TSLP-DC-OX40L axis that initiates and maintains the Th2 cell-mediated inflammatory responses, and therefore, it would be a new therapeutic target for the treatment of allergic disorders.     

TSLP production by epithelial cells exposed to immunodeficiency virus triggers DC-mediated mucosal infection of CD4+ T cells

Mucosal dendritic cells have been implicated in the capture, storage, and transmission of HIV to CD4⁺ T cells as well as in the promotion of HIV replication in activated CD4⁺ T cells during the cognate T-cell and DC interaction. We report that HIV induces human genital mucosal epithelial cells to produce thymic stromal lymphopoietin (TSLP) via activation of the NFκB signaling pathway. The TSLP secreted by HIV exposed epithelial cells activated DC, which promoted proliferation and HIV-1 replication of co-cultured autologous CD4⁺ T cells. In rhesus macaques, we observed dramatic increases in TSLP expression concurrent with an increase in viral replication in the vaginal tissues within the first 2 weeks after vaginal SIV exposure. These data suggest that HIV-mediated TSLP production by mucosal epithelial cells is a critical trigger for DC-mediated amplification of HIV-infection in activated CD4⁺ T cells. The cross talk between mucosal epithelial cells and DC, mediated by HIV-induced TSLP, may be an important mechanism for the high rate of HIV infection in women through the vaginal mucosa.     

Different IL‐5 and IFN‐γ Production from Peripheral Blood T‐Cell Subsets in Atopic and Nonatopic Asthmatic Children

Defective Th1 and enhanced Th2‐type cytokine responses have been implicated in the development of atopic disease. However, the immunopathology of nonatopic asthma, especially in children, remains unclear, and there have been few studies to compare the cytokine profile in peripheral blood T‐cell subsets between atopic and nonatopic asthmatic children. To document whether atopic asthmatic children have a cytokine imbalance and to compare the cytokine profile between atopic and nonatopic asthmatic children, we investigated the interleukin (IL)‐5‐producing and interferon (IFN)‐γ‐producing T‐cell subsets from peripheral blood mononuclear cells (PBMC). The percentages of IFN‐γ‐producing CD4⁺ and CD8⁺ T cells from atopic asthmatic children were decreased, but those in nonatopic asthmatic children were not decreased. In both groups of asthmatic children, the percentages of IFN‐γ‐producing CD4⁺ T cells were inversely correlated with the peripheral blood eosinophils and had a significant correlation with airway responsiveness (PC₂₀). Thus, we found that the mechanism underlying allergic inflammation of nonatopic asthma is not simple a Th1/Th2 cytokine imbalance. Considering the inverse relationship between IFN‐γ‐producing CD4⁺ T cells and eosinophilia or airway hyperresponsiveness, IFN‐γ from CD4⁺ T cells may play an important role in allergic inflammation and airway hyperresponsiveness in asthmatic children.     

Increased expression of CD86 and reduced production of IL-12 and IL-10 by monocyte-derived dendritic cells from allergic asthmatics and their effects on Th1- and Th2-type cytokine balance

BACKGROUND: In allergic asthma, allergen-specific T cells have a Th2-biased phenotype, and it is thought that dendritic cells (DCs) contribute to the induction of allergic immune responses. Therefore, we hypothesized that DCs from allergic asthmatics and healthy donors differ with regard to their preference to induce Th1 or Th2 immune responses. OBJECTIVES: To investigate differences in DC-expressed costimulatory molecules and DC-secreted cytokines between allergic asthmatics and healthy donors, and their influence on the Th1- and Th2-type cytokine balance. METHODS: Circulating monocytes from patients with allergic asthma and healthy donors were cultured with GM-CSF and IL-4, respectively, for 5 days and subsequently with lipopolysaccharide for 2 days to create mature DCs (mDCs). CD1a, CD83, CD40 and CD86 expression on mDCs was examined using a fluorescence-activated cell sorter. IL-12 and IL-10 secreted by mDCs were measured by ELISA. Na?ve cord blood T cells were primed by mDCs from two groups, and IL-4 and IFN-gamma production by polarized T-helper cells (Th) was measured by ELISA. RESULTS: (1) CD86 expression on mDCs from allergic asthmatics was higher than that from healthy donors. (2) IL-12, IL-12p40 and IL-10 production by mDCs from allergic asthmatics was significantly lower than that from healthy donors, respectively. (3) IL-4 production by Th cells primed by mDCs from allergic asthmatics was increased compared with that from healthy donors. CONCLUSIONS: mDCs from allergic asthmatics preferentially priming na?ve T cells towards Th2-cell development might be due to increased expression of CD86 and reduced production of IL-12 and IL-10.     

Modèle expérimental de dermatite atopique

Skin lesions in the allergic form of atopic dermatitis (AD) are induced by allergen-specific T cells which infiltrate the skin at the site of allergen exposure. The pathophysiology of atopic dermatitis is not entirely defined. Although Th2-type CD4⁺ T cells appear to be crucial in AD pathophysiology, little is known about the contribution of CD8⁺ T cells in the development of the allergic skin inflammation. In the present study, we have developed a mouse model of allergen-induced AD and we have analyzed the respective roles of CD8⁺ and CD4⁺ T cells in the development of AD skin lesions. In sensitized mice, CD8⁺ T cells are rapidly and transiently recruited to the allergen-exposed site and initiate the inflammatory process, leading to skin infiltration with eosinophils and Th1/Th2 producing cells. CD8⁺ T cell-depleted mice show no inflammation, demonstrating that these cells are mandatory for the development of AD. In contrast, CD4⁺ T cell-depleted mice develop a severe form of eczema. Furthermore, adoptive transfer of CD8⁺ T cells from sensitized mice into naive recipient mice leads to skin inflammation soon after allergen exposure. These data indicate that allergen-primed CD8⁺ T cells are required for the development of AD-like lesions in mice. Ongoing studies may allow us to confirm these findings in humans.     

Helminth products bypass the need for TSLP in Th2 immune responses by directly modulating dendritic cell function

Thymic stromal lymphopoietin (TSLP) is an interleukin (IL)-7-like cytokine, mainly expressed by epithelial cells, and key to the development of allergic responses. The well-documented involvement of TSLP in allergy has led to the conviction that TSLP promotes the development of inflammatory Th2 cell responses. However, we now report that the interaction of TSLP with its receptor (TSLPR) has no functional impact on the development of protective Th2 immune responses after infection with 2 helminth pathogens, Heligmosomoides polygyrus and Nippostrongylus brasiliensis. Mice deficient in the TSLP binding chain of the TSLPR (TSLPR^−/−) exhibited normal Th2 cell differentiation, protective immunity and memory responses against these two distinct rodent helminths. In contrast TSLP was found to be necessary for the development of protective Th2 responses upon infection with the helminth Trichuris muris (T. muris). TSLP inhibited IL-12p40 production in response to T. muris infection, and treatment of TSLPR^−/− animals with neutralizing anti-IL-12p40 monoclonal antibody (mAb) was able to reverse susceptibility and attenuate IFN-γ production. We additionally demonstrated that excretory-secretory (ES) products from H. polygyrus and N. brasiliensis, but not T. muris, were capable of directly suppressing dendritic cell (DC) production of IL-12p40, thus bypassing the need for TSLP. Taken together, our data show that the primary function of TSLP is to directly suppress IL-12 secretion, thus supporting Th2 immune responses.CD4⁺ T cells can differentiate into Th1, Th2, Th17, and Treg subsets, whose different immunological functions are associated with the production of particular cytokines (1). Of these subsets, Th2 cells play a pivotal role in immunity against helminth infection and are responsible for the pathology associated with allergic disorders (2, 3). Th2 cells typically produce IL-4, IL-5, IL-13, and IL-9 resulting in antibody-isotype switching to IgE, eosinophilia, basophilia, mucin production, and smooth muscle cell hyperreactivity (1).Extensive work has highlighted the key polarizing factors underlying the development of Th1, Th2, Th17, and Treg cells. IL-4 acts as both an effector cytokine and a Th2-polarizing factor (4, 5), although the early signals influencing T cell IL-4 production remain unclear. TSLP activates human DC to up-regulate costimulatory molecules, produce Th2 cell-attracting chemokines, and to promote the production of IL-4, IL-5, IL-13, and TNF-α, but not IL-10, by naïve CD4⁺ T cells (6, 7). TSLP simultaneously fails to activate DC IL-12 secretion (6, 7) and can even inhibit LPS-induced IL-12 production by murine DC in vitro (8, 9). More recently, TSLP has been reported to act directly on naïve mouse CD4⁺ T cells to promote IL-4 production in vitro (10), and to promote Th2 cytokine production by skin-infiltrating effector T cells in vivo (11). Consistent with its role in Th2 differentiation and effector function, TSLPR^−/− mice exhibit strongly attenuated allergic airway (12, 13) and skin inflammation (11), whereas over-expression of TSLP in lung epithelial cells or keratinocytes causes spontaneous allergic inflammation within the respective tissues (13, 14).In the current study, we investigated the impact of TSLP-TSLPR signaling on protective Th2 immune responses against the helminths H. polygyrus and N. brasiliensis, of the Trichostrongyloidea superfamily and T. muris, of the Trichineloidea superfamily. Protective immunity against all 3 helminths requires Th2 immune responses and is abrogated in the absence of Stat6-mediated IL-4/IL-13 signals (15–18). H. polygyrus and N. brasiliensis elicit strong Th2 immune responses in most mouse strains investigated (19). In contrast, the response elicited against T. muris is highly dependent on the genetic background of the host, with resistance or susceptibility tightly correlating with the generation of a Th2 and Th1 immune response, respectively (20, 21). Surprisingly, we found that TSLPR signaling had no detectable impact on H. polygyrus-induced Th2 polarization and only a minor impact on N. brasiliensis-induced CD4⁺ T cell cytokine production. In addition, TSLPR signaling had no impact on Th2 memory responses and did not alter the ability of mice to expel either helminth after secondary infection. In contrast, TSLPR signaling was necessary to prevent IL-12p40 production after T. muris infection, and lack of TSLPR signaling led to impaired protective Th2 responses. Secreted products from H. polygyrus and N. brasiliensis, but not T. muris, were found to modulate DC function in vitro, such that these cells were refractory to LPS-induced production of the proinflammatory cytokine IL-12p40. These data indicate that particular helminths can directly modulate host DC to suppress IL-12p40 production and thus render TSLP redundant for the development of Th2 immune responses.     

The Decreased CD4+CD25+ FoxP3+ T Cells in Nonstimulated Allergic Rhinitis Patients Sensitized to House Dust Mites

Objective. Regulatory (CD4⁺CD25⁺) T cells have been shown to play an important role in the development of allergic diseases. This study aims to investigate CD4⁺CD25⁺ T cells, Forkhead box P3 (FoxP3⁺ cells), and T-helper 1/T-helper 2 (Th1/Th2) cytokines in newly diagnosed allergic rhinitis (AR) patients. Methods. Altogether, 10 subjects with AR and 12 age-matched nonallergic healthy subjects were included in this study. CD4⁺CD25⁺ T cells, FoxP3⁺ T cells in peripheral blood mononuclear cells (PBMCs) were evaluated by flow cytometry, and the Th1/Th2 cytokine levels were determined by cytometric bead array immunoassay in both PBMC supernatants and nasal lavage fluids. Results. The percentage of CD4⁺CD25⁺ T cells were significantly higher, whereas the percentage of FoxP3⁺ cells were lower in AR patients compared with healthy subjects. In PBMC culture supernatants, interleukin-10 (IL-10) levels were significantly lower (p = .012), whereas IL-4, IL-5, and tumor necrosis factor-α (TNF-α) levels in nasal lavage fluids were higher in AR patients compared with healthy subjects (p = .026, p = .015, p = .03, respectively). Conclusions. Our findings indicate that decrease in CD4⁺CD25⁺FoxP3⁺ T cell fraction and diminished levels of IL-10 are noteworthy without allergen stimulation in house dust mite AR patients.     

Sublingual administration of liposomes enclosing alpha-galactosylceramide as an effective adjuvant of allergen immunotherapy in a murine model of allergic rhinitis

BackgroundSublingual immunotherapy (SLIT) is an established efficacious approach for the treatment of allergic rhinitis (AR). However, SLIT requires a long administration period to establish stable and adequate responses. This study investigated the efficacy of the sublingual administration of an allergen with liposomes enclosing α-GalCer (α-GC-liposome) as a potential adjuvant in mice with AR.MethodsMice with AR induced by OVA received the sublingual administration of OVA, α-GC-liposomes, or OVA plus α-GC-liposomes for 7 days. After nasal re-challenge with OVA, nasal symptoms were evaluated. The serum levels of OVA-specific Ig, the cytokine production of CD4⁺ T cells in the cultures of cervical lymph node (CLN) cells, and the gene expression of CLNs were analyzed.ResultsAlthough IL-4, IL-5 and IL-13 production from CD4⁺ T cells in CLN cells was significantly inhibited by the sublingual administration of OVA alone in mice with AR induced by OVA, their nasal symptoms were not significantly diminished. However, the combined sublingual administration of α-GC-liposomes and OVA completely suppressed nasal symptoms, downregulated Th2 and Th17 type cytokine production in CD4⁺ T cells as well as Th2 and Th17 gene expressions, and upregulated Th1 type cytokine production as well as Th1 gene expressions in CLN cells. Additionally, the serum levels of specific IgG2a were promoted, and specific IgE and IgG1 were inhibited.ConclusionsOur findings suggest that the sublingual administration of an allergen with α-GC-liposomes as an adjuvant might increase the therapeutic efficacy and effectiveness of this treatment method.     

Dendritic cells frequency and phenotype in Egyptian type 1 diabetic patients

This study was performed to investigate changes in the dendritic cells (DCs) frequency and phenotype in the peripheral blood in Egyptian Type 1 diabetic children. Also to study the level of B, T lymphocytes, activated T lymphocytes, and costimulatory molecules expression on B lymphocytes. Twenty five children with T1DM and 25 healthy controls were enrolled. Flow cytometric detection of DCs, B-lymphocytes and T-lymphocytes, CD19⁺CD80⁺, CD19⁺CD86⁺, CD19⁺HLA-DR⁺ and CD3⁺ HLA-DR⁺ was preformed. The frequencies of monocytoid dendritic cells (mDCs) and plasmacytoid dendritic cells (pDCs) were significantly decreased in diabetic patients than the controls and the mDCs/pDCs ratio was significantly higher in diabetic patients. The expression of costimulatory molecules CD80 and CD86 on the entire DCs was significantly higher in diabetic children. The frequency of pDCs was negatively correlated with the age in diabetic patients and positively correlated with the level of insulin C-peptide. The percentage of CD80 expressing B lymphocytes and of activated T lymphocytes was significantly higher in the patients. Dendritic cells are reduced in number and display more mature phenotype in T1DM children. The higher expression of CD80 on B lymphocytes and activation of T lymphocytes may reflect the ongoing autoimmune process in this disease. Modulation of the DCs could have beneficial effect in T1DM.     

Functional and phenotypic characterization of CD8+CD28+ and CD28- T cells in atopic individuals sensitized to Dermatophagoides pteronyssinus

BackgroundCD8⁺ T suppressor cells may play a role in immunoregulation. Recent studies have characterized this population by the lack of the CD28 molecule. These CD8⁺CD28⁻ T cells differ phenotypically and functionally from CD8 + CD28 + T cells. Little is known about CD8 + CD28^– cells in atopy. Our aim was to analyze the phenotype and functional properties of CD8 + CD28⁻ T cells in atopic and non-atopic individuals.MethodsPeripheral blood mononuclear cells (PBMC) were obtained after density gradient centrifugation. CD8 + CD28⁻ and CD8 + CD28 + T cells were isolated using immunomagnetic beads. Relative percentagesof these cells and expression of several phenotypic markers were analyzed by flow cytometry. Proliferation was assessed by thymidine incorporation in isolated populations and in co-cultures with PBMC using Dermatophagoides pteronyssinus as stimulus. Cytokine synthesis was evaluated in culture supernatants by cytometric bead array.ResultsThe relative percentages of CD8⁺CD28⁻ T cells and their phenotypic expression in atopic and non-atopic volunteers were not significantly different. However, CD8 + CD28⁻ T cells showed greater proliferation than did CD8⁺CD28⁺ T cells when stimulatedwith D. pteronyssinus, although cytokine synthesis patterns were similar. CD8⁺CD28⁻ co-cultures with PBMC showed greater proliferation than CD8⁺CD28⁺ T cell co-cultures, but cytokine synthesis patterns were not different.ConclusionsOur data confirm phenotypic and functional differences between CD28⁺ and CD28⁻ T cells, irrespective of atopic status. Purified human CD8⁺CD28⁻ T cells, freshly isolated from peripheral blood, do not have suppressor properties on allergen- specific proliferation or on cytokine synthesis in PBMC.     

A potential immunopathogenic role for reduced IL-35 expression in allergic asthma

Objective: Allergic asthma is a chronic airway inflammation resulting from an imbalance of T helper (Th) cell responses to allergens. Interleukin (IL)-35 has been shown to have potent immunoregulatory properties. Whether IL-35 participates in the immunopathogenesis of allergic asthma patients is still unknown. Methods: CD4⁺ T cells and CD4⁺CD25^? T cells were obtained from peripheral blood mononuclear cells (PBMCs) using magnetic separation. The concentration of IL-35 in plasma was measured by enzyme-linked immunosorbent assay (ELISA). The mRNA expression levels of the IL-35 subunits, EBI3 and IL-12p35, were detected by quantitative real-time PCR (qPCR). The proliferative responses of CFSE-labeled CD4⁺CD25^? T cells in the presence or absence of rhIL-35 were evaluated by flow cytometry. Cytokine production of activated CD4⁺CD25^? T cells was examined by flow cytometry and ELISA. Results: IL-35 protein and mRNA levels were decreased in allergic asthmatics. The frequencies of CD4⁺CD25⁺Foxp3⁺ Tregs and CD4⁺IL-12p35⁺ T cells in allergic asthma patients were lower than in healthy controls. Moreover, the addition of rhIL-35 suppressed CFSE⁺CD4⁺CD25^? T cell proliferation in vitro in a dose-dependent manner, and the suppression induced by rhIL-35 was associated with decreases in IL-4 but not IFN-γ and IL-17 production of activated CD4⁺CD25^? T cells. The increased level of Th1/Th2 was observed in allergic asthmatics in the presence of rhIL-35. Conclusions: Our data suggest that IL-35 can effectively suppress the proliferation and IL-4 production of activated CD4⁺CD25^? T cells in allergic asthma, and that IL-35 may be a new immunotherapy for asthma patients.     

Thy1+IL-7+ lymphatic endothelial cells in iBALT provide a survival niche for memory T-helper cells in allergic airway inflammation

Memory CD4⁺ T helper (Th) cells are central to long-term protection against pathogens, but they can also be pathogenic and drive chronic inflammatory disorders. How these pathogenic memory Th cells are maintained, particularly at sites of local inflammation, remains unclear. We found that ectopic lymphoid-like structures called inducible bronchus-associated lymphoid tissue (iBALT) are formed during chronic allergic inflammation in the lung, and that memory-type pathogenic Th2 (Tpath2) cells capable of driving allergic inflammation are maintained within the iBALT structures. The maintenance of memory Th2 cells within iBALT is supported by Thy1⁺IL-7–producing lymphatic endothelial cells (LECs). The Thy1⁺IL-7–producing LECs express IL-33 and T-cell–attracting chemokines CCL21 and CCL19. Moreover, ectopic lymphoid structures consisting of memory CD4⁺ T cells and IL-7⁺IL-33⁺ LECs were found in nasal polyps of patients with eosinophilic chronic rhinosinusitis. Thus, Thy1⁺IL-7–producing LECs control chronic allergic airway inflammation by providing a survival niche for memory-type Tpath2 cells.Immunological memory is a key feature of adaptive immunity, and memory CD4⁺ T cells are crucial for this system to function. In the absence of memory CD4⁺ T cells, B-cell responses, including the generation of high-affinity memory B cells and long-lived plasma cells, are markedly impaired (1, 2). Moreover, CD4⁺ T cells are required for the maintenance of memory CD8⁺ T cells (3). In addition to their protective functions, memory CD4⁺ T cells also play a central role in the pathogenesis of chronic inflammatory disorders, including asthma and atopic dermatitis (4, 5). IL-5–producing memory Th2 cell subsets are critical for the pathology of allergic inflammation, and function as “memory-type pathogenic Th2 cells” (6) (Tpath2 cells). Given the importance of memory CD4⁺Th cells, little is known about how memory CD4⁺Th cells are maintained in the body, especially at local inflammatory sites where they persist and induce chronic inflammation.Bronchus-associated lymphoid tissue (BALT) develops as a normal mucosal lymphoid tissue observed in the lung in certain mammalian species, including rabbits and rats, but not humans or mice (7). In humans and mice, BALT is induced in the lung in response to inflammation caused by various infectious organisms, and is called inducible BALT (iBALT) (8). iBALT consists of separate B-cell and T-cell areas, with the presence of resident dendritic cells (DCs), follicular DCs (FDCs), high endothelial venules (HEVs), and lymphatics (8, 9). Some similarities between the processes of iBALT generation and the preprogrammed development of conventional lymph nodes have been reported (10). For instance, the chemokine CXCL13 (the ligand for CXCR5) and the chemokines CCL19 and CCL21 (ligands for CCR7) are involved in formation of iBALT as well as lymphoid neogenesis (11). Moreover, mice deficient in the chemokine receptor CCR7 appear to spontaneously develop BALT together with excessive formation of secondary lymphoid organs without being exposed to immunological stimulation (12). In humans, iBALT formation has been identified in patients with chronic inflammatory diseases such as rheumatoid arthritis, tuberculosis, and chronic obstructive pulmonary diseases (13–15). Despite increasing evidence of the correlation between iBALT formation and the severity of chronic inflammatory diseases in the lung, the pathophysiological roles of iBALT remain unknown.Chronic rhinosinusitis (CRS) involves long-term inflammation of the nasal and paranasal sinus mucosa (16). CRS is one of the most common comorbidities among patients with asthma, and the comorbidities share similar inflammatory processes and histopathology (17). CRS has been recently divided into two subgroups: with and without nasal polyps (18). The majority of cases of CRS with nasal polyps show Th2-type inflammation with prominent accumulation of eosinophils in the nasal polyps and are thus called eosinophilic CRS (ECRS) (19). Histological analysis of nasal polyps of patients with ECRS revealed massive tissue eosinophilia as well as infiltrating lymphocytes (20).Herein, we demonstrate that Tpath2 cells are efficiently maintained in iBALT in the lung in a chronic allergic airway inflammation model. We identified Thy1⁺IL-7–producing lymphatic endothelial cells (LECs) in the iBALT structures that support the maintenance of memory Th2 cells. In humans, lymphatics with IL-7⁺IL-33⁺ LECs, together with accumulation of ectopic lymphoid tissues containing memory CD4⁺ T cells, were found in nasal polyps of patients with ECRS. Thus, in humans and mice, specialized Thy1⁺IL-7⁺IL-33⁺ LECs appear to maintain pathogenic memory CD4⁺ T cells within iBALT. Our study provides new insight into the mechanism through which memory-type pathogenic Th cells are maintained at local inflammatory sites and defines therapeutic targets for the treatment of chronic airway inflammation.     

Effects of anti-allergic drugs on T cell-mediated nasal hyperresponsiveness in a murine model of allergic rhinitis

Background

We have recently demonstrated that T cell-mediated nasal hyperresponsiveness (NHR) is a representative pathophysiological feature of allergic rhinitis (AR). Although several anti-allergic drugs are used for the treatment of AR, the efficacy of these drugs on T cell-mediated NHR have not been elucidated. In these studies we investigated the effects of dexamethasone (Dex), montelukast (Mk), and chlorpheniramine (Chl) on NHR in antigen-immunized and antigen-specific Th2 cell-transferred mice.

Differentiation of naive human CD4+ T cells into Th2 cells: The role of prostaglandin E2

T-helper (Th) 2 cells, which produce interleukin (IL)-4, IL-5, IL-10 and IL-13 upon stimulation of their T cell receptors, play an important role in the development of human allergic diseases. However, the precise mechanism involved in the differentiation of Th2 cells is not well understood compared with that of Th1 cells. The selective differentiation of Th1 or Th2 subsets is established during priming under the influence of a variety of factors. Prostaglandin E₂ (PGE₂) is one of those factors. Prostaglandin E₂ produced by antigen presenting cells directly affects the naive CD4⁺ T cells, causing them to differentiate into Th2 cells. This effect is mediated by the elevation of cyclic adenosine monophosphate (cAMP) at the early stage of T cell activation. IL-4 and PGE₂ lead naive CD4⁺ T cells to differentiate into Th2 cells cooperatively, by distinct signal transduction. Both PGE2 and IL-4 inhibit the hypomethylation of the proximal regulatory regions of the genomic IFN-γ gene, whose hypomethylation has been suggested as being important for the IFN-γ production by CD4⁺ T cells stimulated through their antigen receptors. Prostaglandin E₂ facilitates Th2 differentiation of naive CD4⁺ T cells by acting not only on T cells directly but also on antigen presenting cells by inhibiting their IL-12 production. The production of PGE₂ by monocytes is increased significantly in allergic patients. These results, taken collectively, suggest that PGE₂ plays an important role in facilitating the differentiation of Th2 cells in vivo.