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Background Seasonal allergic rhinitis is a chronic inflammation in the nasal mucosa triggered by inhaled aeroallergens. The inflammatory reaction is controlled by allergen-specific T cells, but where and how these T cells become activated is not fully understood. Objectives We wanted to determine whether allergen-specific T-helper (Th) 2 cells are residing in the nasal mucosa under steady-state conditions outside of the pollen season and, if so, whether these cells are activated locally in response to allergen challenge. Methods Mucosal biopsies from the lower turbinate were obtained out of season from patients with either birch- or grass-pollen-allergic rhinitis and from healthy controls. Cultured explant samples were challenged with relevant pollen extract or with a mix of overlapping 20-mer peptides derived from the sequence of the major birch allergen, Betula verrucosa (Bet v) 1. After 24 h, culture medium was harvested for multiplex cytokine and tryptase analysis. Results Significant amounts of interleukin ( IL)-5 were secreted from resident cells in response to ex vivo allergen challenge in the allergic group only. No increase was observed for the other cytokines measured. Production of IL-5 in response to both extract and the Bet v1-derived peptide mix strongly suggested that T cells were a major source of IL-5. Conclusion Our explant model indicated that local presentation of antigen to resident allergen-specific Th2 cells is the early event in the pathogenesis of allergic rhinitis. These findings identify possible cellular targets for anti-inflammatory treatment. [ABSTRACT FROM AUTHOR]

It has been suggested that Foxp3 regulatory T (Treg) cells inhibit allergic inflammation in humans by suppressing the activation of allergen-specific effector T cells. Whether this occurs at the site of allergen exposure has not been determined. To determine the occurrence of Foxp3 Treg cells in the nasal mucosa of allergic rhinitis (AR) patients and non-allergic controls after a nasal allergen challenge. Pollen-allergic patients ( n=18) and non-allergic volunteers ( n=7) were challenged locally with pollen extract or placebo for 7 days outside the pollen season. Mucosal biopsies were obtained from the inferior turbinate on days 0, 1 and 7 and subjected to multi-colour immunofluorescence and blood was drawn for eosinophil counts on days 0, 2, 5 and 7. Only AR patients receiving pollen extract experienced typical allergic symptoms and demonstrated increased levels of eosinophils in peripheral blood and nasal mucosa. In allergic patients, a transient early increase (day 1) in CD3 T cells was observed in the nasal mucosa, followed by a significant increase of Foxp3 T cells at day 7. No changes were found in the control group. The majority of Foxp3 cells co-expressed CTLA-4, CD25 and CD4, and a substantial fraction expressed the proliferation marker Ki67. Experimentally induced inflammation in AR patients leads to an early inflammatory response followed by accumulation of Foxp3 T cells in the nasal mucosa. Our findings are similar to that observed in allergic airways of experimental mice, which suggest that Treg cells are operative in allergic upper airway inflammation. It should be explored whether Treg cells accumulating in the nasal mucosa could be targets for therapeutic intervention. Cite this as: I. Skrindo, C. Scheel, F.-E. Johansen and F. L. Jahnsen, Clinical & Experimental Allergy, 2011 (41) 954-962. [ABSTRACT FROM AUTHOR]

Background It has been suggested that allergic diseases are caused by defective suppression of allergen-specific Th2 cells by CD4+CD25+ regulatory T cells. However, such studies have been hampered by the difficulty in distinguishing regulatory T cells from CD25-expressing activated T cells. Recently, it was shown that conventional T cells expressed high levels of CD127, whereas regulatory T cells were CD127lo, allowing discrimination between these distinct T cell subpopulations. Objective The aim of this study was to study whether the putative regulatory subset defined as CD4+CD25+CD127lo was involved in grass pollen-reactive T cell responses. Methods Peripheral blood mononuclear cells (PBMCs) were obtained from allergic donors and non-atopic controls out of season. Grass pollen-induced cytokine production and proliferation were compared in cultures of undepleted cells and cells depleted of CD4+CD25+, CD4+CD25+CD127hi or CD4+CD25+CD127lo T cells. Results Undepleted cell cultures from allergic patients showed significantly increased proliferation and Th2 cytokine production compared with non-atopic controls. Depletion of all CD25+ T cells did not increase cytokine production or proliferation, and more importantly, no increase in Th2 cytokine production or proliferation was observed in cell cultures depleted of CD4+CD25+CD127lo cells (putative regulatory T cells) compared with undepleted PBMCs in both the allergic and the non-atopic group. Conclusion Our study showed that T cells from grass pollen-allergic patients and non-atopic controls responded very differently to grass pollen extract, but this difference could not be explained by differences in regulatory T cell function. Further studies are needed to understand the importance of regulatory T cells in allergy. [ABSTRACT FROM AUTHOR]

Background: In early childhood, the ability to mount protective immune responses in the airways is impaired, with increased risk of allergic sensitisation to inhaled allergens. Antigen presenting cells (APC) and regulatory T cells (Treg) are important modifiers of T cell immunity but little is known about their distribution in bronchial mucosa at this age. Here the subset distribution of APC and the appearance of Foxp3+ Treg and bronchus associated lymphoid tissue (BALT) were examined immunohistochemically in children less than 2 years of age with chronic asthma-like symptoms of the lower airways. Methods: mmunophenotyping was performed in situ on bronchial biopsy specimens obtained from 45 infants, 4-23 months of age, under investigation for airway disease. Results: A well developed HLA-DR+ network of APC was present in all samples, approximately 50% of the cells being CD68+ macrophages and the remainder various subsets of dendritic cells. The density of HLA-DR+ cells increased significantly with age but was not related to atopy, clinical symptoms or lung function. Comparing the density of APC subsets and clinical parameters, only the number of intraepithelial CD1a+ dendritic cells was significantly increased in infants who had recently suffered a respiratory infection. BALT structures were identified in 22 children, with no relation to lung function, atopic status or human rhinovirus positivity. Plasmacytoid dendritic cells and Foxp3+ Treg were located primarily within these isolated lymphoid follicles. Conclusion: A bronchial network of dendritic cells and macrophages develops quite rapidly after birth, apparently independent of clinical symptoms or atopy. The high frequency of BALT structures containing putative tolerogenic dendritic cells and Treg suggests that these lymphoid follicles play an important role in bronchial immune homeostasis during infancy. [ABSTRACT FROM AUTHOR]

Regulatory T cells (Tregs) may inhibit immunity against cancer. Induction and expansion of Tregs in the immunosuppressive microenvironment created by a growing tumour appear to be one of the mechanisms by which it can evade host defence. We studied the impact of CD25+ Tregs in a B cell lymphoma model in which Rag2–/– mice received adoptive transfer of wild-type spleen cells with or without CD25+ cells, and concurrently subcutaneous inoculation of the B cell lymphoma cell line A20. We also examined the effect of engaging the glucocorticoid-induced tumour necrosis factor receptor (GITR) − an approach reported previously to abrogate the suppressive effects of Tregs. Mice that received spleen cells depleted of CD25+ Tregs showed significantly slower tumour growth and increased survival compared with mice that received unsorted spleen cells. The Treg-depleted group also had significantly more CD8+ T cells infiltrating the tumours and higher levels of serum immunoglobulin G subclasses. The anti-GITR treatment had no significant effect on tumour growth, survival or immunoglobulin production. In the CD25-depleted group four of 10 mice developed clinical signs of autoimmunity, in contrast to none in the non-depleted group. Forkhead box P3+ T cells were found in tumour-draining lymph nodes in mice in the CD25-depleted group, suggesting an in vivo induction or expansion of rare transferred donor Tregs. Thus, our study showed that removal of CD25+ Tregs enhanced anti-tumour immunity against local growth of a B cell lymphoma and that induction or expansion of Tregs could be one mechanism by which the growing tumour evades immune surveillance. [ABSTRACT FROM AUTHOR]

Celiac disease is a chronic small intestinal inflammation driven by gluten-reactive T cells of the intestinal mucosa. These T cells are HLA-DQ2 or -DQ8 restricted, and predominantly recognize gluten peptides that are deamidated by the enzyme transglutaminase 2 (TG2). Our recent results strongly suggest that duodenal CD11c+ dendritic cells (DC) are directly involved in T cell activation in the celiac lesion. The aim of this study was to investigate whether surface-associated TG2 could be involved in receptor-mediated endocytosis of gluten peptides, a process that may contribute to the preferential recognition of deamidated peptides. We found that both monocyte-derived DC and local CD11c+ DC in the duodenal mucosa expressed cell surface-associated TG2. As phenotypic characterization of CD11c+ DC in the celiac lesion suggests that these cells may be derived from circulating monocytes, we used monocyte-derived DC in functional in vitro studies. Using a functional T cell assay, we obtained evidence that cell surface-associated TG2 is endocytosed by monocyte-derived DC. However, we were unable to obtain evidence for a role of surface TG2 in the loading and subsequent generation of deamidated gluten peptides in these cells. [ABSTRACT FROM AUTHOR]

Inherent properties of dendritic cell (DC) subsets are important in the regulation of naïve T-cell differentiation (e.g. Th1 versus Th2 cells), whereas effector memory T cells are believed to produce a fixed cytokine repertoire independent of the type of antigen presenting cell. Here we show that two distinct human DC subsets, plasmacytoid DC (PDC) and myeloid CD1 lc+ DC, induced autologous mumps virus-specific memory CD4+ T cells to produce markedly different cytokine patterns upon antigen stimulation. PDC stimulated the T cells to produce γ-interferon (IFN-γ) and interleukin-(IL)-10, whereas CD1 1c+ DC induced lower levels of IFN-γ, virtually no IL-10, but significant levels of IL-5. Analysis of intracellular cytokine production showed simultaneous production of IL-10 and IFN-γ in mumps-specific T cells activated by PDC, a cytokine pattern similar to that described for Th1-like regulatory cells. Introduction of CpG oligodeoxynucleotides in PDC/T-cell co-cultures had synergistic effect on virus-dependent IFN-γ production, whereas the other cytokines remained unchanged. Together, our results show that the type of DC involved in reactivation of previously primed T cells may have significant impact on the resulting cytokine response and suggest that targeting of viral antigens and adjuvant to specific DC subsets should be considered in the design of therapeutic antiviral vaccines. [ABSTRACT FROM AUTHOR]

Lymphocyte recruitment to peripheral tissues is fundamental for immune surveillance and homeostasis, but the chemokines and chemokine receptors responsible for tissue-specific homing of T cells to the upper airway mucosa have not been determined. To address this, we analyzed the chemokines expressed in the normal human nasal mucosa and found that CCL28 is preferentially expressed at a high level on the lumenal face of vascular endothelial cells in the mucosa. Analysis of the cognate chemokine receptors revealed that close to 50% of the CD4+ T cells in the human nasal mucosa expressed the CCL28 receptor CCR3, whereas CCR3 was hardly detectable on T cells in the small intestine and skin. In the circulation, CCR3+ T cells comprised a small subset that did not express homing receptors to the intestine or skin. Moreover, depletion of CCR3+CD4+ T cells abrogated the proliferative response of human blood CD4+ T cells against the opportunistic nasopharyngeal pathogen Haemophilus influenzae, indicating that the CCR3+CD4+ T-cell subset in the circulation contains antigen specificities relevant for the upper airways. Together, these findings indicate that CCL28-CCR3 interactions are involved in the homeostatic trafficking of CD4+ T cells to the upper airways. [ABSTRACT FROM AUTHOR]