Human Th17 cells

The discovery in mice of a new lineage of CD4+ effector T helper (Th) cells that selectively produce IL-17 has provided exciting new insights into immune regulation, host defence, and the pathogenesis of autoimmune and other chronic inflammatory disorders. This population of CD4+ Th cells, which has been termed 'Th17', indeed plays an apparently critical role in the pathogenesis of some murine models of autoimmunity. Interestingly, murine Th17 cells share a common origin with Foxp3+ T regulatory cells, because both populations are produced in response to transforming growth factor-β, but they develop into Th17 cells only when IL-6 is simultaneously produced. Initial studies in humans have confirmed the existence of Th17 cells, but they have shown that the origin of these cells in humans differs from that in mice, with IL-1β and IL-23 being the major cytokines responsible for their development. Moreover, the presence in the circulation and in various tissues of Th cells that can produce both IL-17 and interferon-γ, as well as the flexibility of human Th17 clones to produce interferon-γ in addition to IL-17 in response to IL-12, suggests that there may be a developmental relationship between Th17 and Th1 cells, at least in humans. Resolving this issue has great implications in tems of establishing the respective pathogenic roles of Th1 and Th17 cells in autoimmune disorders. In contrast, it is unlikely that Th17 cells contribute to the pathogenesis of human allergic IgE-mediated disorders, because IL-4 and IL-25 (a powerful inducer of IL-4) are both potent inhibitors of Th17 cell development

Heterogeneity of human effector CD4+ T cells

For many years the heterogeneity of CD4+ T-helper (Th) cells has been limited to Th1 and Th2 cells, which have been considered not only to be responsible for different types of protective responses, but also for the pathogenesis of many disorders. Th1 cells are indeed protective against intracellular microbes and they are thought to play a pathogenic role in organ-specific autoimmune and other chronic inflammatory disorders. Th2 cells provide protection against helminths, but are also responsible for the pathogenesis of allergic diseases. The identification and cloning of new cytokines has allowed one to enlarge the series of functional subsets of CD4+ Th effector cells. In particular, CD4+ Th cells producing IL-17 and IL-22, named Th17, have been initially implicated in the pathogenesis of many chronic inflammatory disorders instead of Th1 cells. However, the more recent studies in both humans and mice suggest that Th17 cells exhibit a high plasticity toward Th1 cells and that both Th17 and Th1 cells may be pathogenic. More recently, another two subsets of effector CD4+ Th cells, named Th9 and Th22 cells, have been described, even if their pathophysiological meaning is still unclear. Despite the heterogeneity of CD4+ effector Th cells being higher than previously thought and some of their subsets exhibiting high plasticity, the Th1/Th2 paradigm still maintains a strong validity

Effect of pre-seasonal seasonal treatment with budesonide topical nasal powder in patients with seasonal allergic rhinitis

abstract The efficacy and safety of budesonide nasal powder (Rhinocort Turbuhaler®) in seasonal allergic rhinitis when given only at the onset of symptoms during the pollen season or when also given before the pollen season, were compared. The study was carried out in 364 patients from 14 centres in Italy as a randomized, double-blind, parallel-group, placebo- controlled comparison of five alternative treatment regimens given for 4 weeks during the pre-pollen and early pollen season (PPS) and for 6 weeks during the pollen season (PS). It was concluded that either 200 μ g or 400 μ g of budesonide given once daily PPS provides significant control of symptoms experienced during PPS. The 400 μ g dose, however, also provides additional prophylactic protection against symptoms during early PS. When the pollen season is established, the dose of budesonide may be reduced to 200 μ g

A Case of Chronic Urticaria Due to Dirofharia Infestation

ABSTRACTUrticaria is one of the most common dermatoallergic conditions occurring mainly in children and adolescents and in atopic individuals. The term of chronic idiopathic urticaria (CIU) is used when the pathophysiological mechanisms remain unclear. Chronic infections and parasitic infestations have been suggested to play an important role in the etiology of CIU. In the present paper, we describe a case of chronic, apparently idiopathic urticaria in an adult woman where Dirofilaria has been recognized to play a pathogenic role in the determination of the cutaneous disease

Th2 cells are less susceptible than Th1 cells to the suppressive activity of CD25+ regulatory thymocytes because of their responsiveness to different cytokines

AbstractT-cell clones generated from both CD4+CD25+ and CD8+CD25+ human thymocytes were assessed for their ability to suppress the proliferative response to allogeneic stimulation of type 1 T-helper (Th1) or type 2 T-helper (Th2) clones derived from autologous CD4+CD25- thymocytes. Both CD4+ and CD8+ T-regulatory (Treg) cells completely suppressed the proliferation of Th1 clones but exhibited significantly lower suppressive activity on the proliferation of Th2 clones. The partial suppressive effect on Th2 cells was further reduced by the addition in culture of interleukin-4 (IL-4), whereas it was increased in the presence of an anti–IL-4 monoclonal antibody (mAb). The suppressive activity on Th2 clones was also completely inhibited by the addition of IL-7, IL-9, and IL-15 but not of IL-2, whereas the suppressive effect on Th1 clones was only reverted by the addition of IL-15. Of note, Th2 clones expressed significantly higher amounts of mRNA for IL-4 receptor (IL-4R) and IL-9R α chains than Th1 clones, whereas the expression of mRNA for IL-2R, IL-7R, and IL-15R α chains was comparable. Taken together, these findings demonstrate that Th2 cells have a lower susceptibility than Th1 cells to the suppressive activity of human CD25+ regulatory thymocytes, because they are able to produce, and to respond to, growth factors distinct from IL-2, such as IL-4 and IL-9. (Blood. 2004; 103:3117-3121

IL-10–Producing Infliximab-Specific T Cells Regulate the Antidrug T Cell Response in Exposed Patients

Abstract Infliximab (IFX) is a chimeric mAb that can lead to the appearance of anti-drug Abs. Recent research has identified the presence of circulating IFX-specific T cells in treated patients. The aim of the study was to analyze the functional characteristics of IFX-specific T cells, in particular their capability to produce biologically active regulatory cytokines. Drug-stimulated PBMCs or coculture systems were used to detect memory T cells in treated patients. The cytokines produced by IFX-specific T cells, T cell lines, and T cell clones were evaluated at the mRNA and protein levels. Drug infusion induced an increase in IL-10 serum levels in vivo, whereas other cytokines were unchanged. IL-10 mRNA was higher in IFX-stimulated PBMCs from treated patients compared with untreated patients. When analyzed longitudinally, an early IL-10 mRNA expression was observed. HLA class II–restricted IL-10 production by drug-specific T cells from exposed patients was observed in different experimental settings, such as a coculture system, sorted CD154+ T cells, IFX peptide–stimulated PBMCs, and IFX-specific T cell clones. Finally, IL-10–producing drug-specific T cell clones downregulated the response of autologous effector T cells to IFX. Overall, these findings identify IFX-specific T cells as a source of biologically active IL-10 and suggest interference by IL-10–producing cells in the detection of drug-specific T cells

CXCR3 and α_Eβ₇ integrin identify a subset of CD8+ mature thymocytes that share phenotypic and functional properties with CD8+ gut intraepithelial lymphocytes

Background: We previously demonstrated the existence of two distinct subsets of T cell receptor (TCR)αβ+CD8αβ+ single positive (SP) cells in human postnatal thymus which express the chemokine receptor CCR7 or CXCR3 and migrate in vitro in response to their specific ligands. Aim: To investigate whether these two CD8+ thymocyte subsets had distinct peripheral colonisation. Methods: TCRαβ+CD8+ SP cells were obtained from normal postnatal thymus, mesenteric lymph node (LNs), small bowel, and peripheral blood (PB) specimens. Cells were then evaluated for expression of surface molecules, cytolytic potential, telomere length, and profile of cytokine production. Results: CD8+CCR7+CXCR3− thymocytes exhibited CD62L, in common with those which localise to LNs. In contrast, CD8+CCR7−CXCR3+ thymocytes lacked CD62L but exhibited CD103, similar to intraepithelial lymphocytes (IELs) present in the gut mucosa where the CXCR3 ligand, CXCL10, and the CD103 ligand, E-cadherin, are highly and consistently expressed. In addition, thymocytes and gut CD8+CXCR3+CD103+ cells showed comparable telomere length, which was higher than that of PB CXCR3+CD8+ T cells. However, both of these populations contained perforin and granzyme A, and displayed the ability to produce interferon γ and interleukin 2. Of note, CXCR3 deficient, in comparison with wild-type C57Black/6, mice showed decreased proportions of CD3+CD8αβ+ and increased proportions of CD3+CD8αα+ lymphocytes at gut level. Moreover, adoptive transfer of CD3+CD8αβ+ thymocytes from wild-type into CXCR3 deficient mice resulted in a significant increase in CD3+CD8αβ+ T cells in the gut mucosa but not in other tissues. Conclusions: The results of this study demonstrate the existence of a previously unrecognised subset of TCRαβ+CD8αβ+ SP CXCR3+CD103+ thymocytes which share phenotypic and functional features with CD8+ IELs, thus suggesting the possibility of their direct colonisation of the gut mucosa

Phenotypic and functional features of human Th17 cells

T helper (Th) 17 cells represent a novel subset of CD4+ T cells that are protective against extracellular microbes, but are responsible for autoimmune disorders in mice. However, their properties in humans are only partially known. We demonstrate the presence of Th17 cells, some of which produce both interleukin (IL)-17 and interferon (IFN)-γ (Th17/Th1), in the gut of patients with Crohn's disease. Both Th17 and Th17/Th1 clones showed selective expression of IL-23R, CCR6, and the transcription factor RORγt, and they exhibited similar functional features, such as the ability to help B cells, low cytotoxicity, and poor susceptibility to regulation by autologous regulatory T cells. Interestingly, these subsets also expressed the Th1-transcription factor T-bet, and stimulation of these cells in the presence of IL-12 down-regulated the expression of RORγt and the production of IL-17, but induced IFN-γ. These effects were partially inhibited in presence of IL-23. Similar receptor expression and functional capabilities were observed in freshly derived IL-17–producing peripheral blood and tonsillar CD4+ T cells. The demonstration of selective markers for human Th17 cells may help us to understand their pathogenic role. Moreover, the identification of a subset of cells sharing features of both Th1 and Th17, which can arise from the modulation of Th17 cells by IL-12, may raise new issues concerning developmental and/or functional relationships between Th17 and Th1