While fluconazole is usually

active against Candida albicans, non-Candida albicans species often require more sophisticated approaches. A rapid species diagnosis is therefore desirable and can be provided by fluorescence in situ hybridisation (FISH). However, broad evaluation studies of described probes are largely lacking and the probe panel that has been described is incomplete. As an addition to previously described C. albicans FISH probes, we evaluated published DNA probes for C. glabrata and C. krusei, as well as newly this website designed DNA probes for C. krusei, C. lusitaniae, C. parapsilosis, C. tropicalis, Crypotococcus neoformans and a group of intrinsically fluconazole-resistant Candida species for FISH with 22 reference strains, 23 well-characterised laboratory control strains, 169 isolates from clinical samples and 48 blood cultures. Sensitivity and specificity of >99% were demonstrated for all evaluated BGB324 cost species-specific probes, whereas the probe that binds to a heterogeneous group of intrinsically fluconazole-resistant Candida species correctly identified eight of nine fluconazole-resistant clinical isolates. FISH yielded reliable results using the classical FISH procedure as well as a recently described slide chamber-based method. Given this good sensitivity and specificity, FISH may be applied for rapid identification of yeast in screening analyses, thus

giving the opportunity for more precise targeting of antimycotic therapy. “
“Candida

species are the fourth most common cause of nosocomial bloodstream infections. An increase in the frequency of infections, which have become refractory to standard antifungal therapy, has been observed. Recent studies have shown that the pro-oxidant properties of diphenyl diselenide (PhSe)2, a structurally simple organoselenium compound, can be toxic to yeast. The objective of this work was to study, under non-reactive oxygen species (ROS)-generating conditions, the effect of different organochalcogenide Selleckchem Gemcitabine compounds [(PhSe)2, (PhTe)2, (MeOPhSe)2, (p-Cl-PhSe)2 and (F3CPhSe)2] on growth and germ tube formation by Candida albicans. A decrease in C. albicans growth in the presence of crescent concentrations of (PhSe)2, (PhTe)2 and (MeOPhSe)2 was observed. The organochalcogenide compound concentration needed to inhibit 50% (IC50) of the Candida growth was 0.5–2 and 2–10 μmol l−1, at a cell density of 105 and 106 cells ml−1, respectively. The compounds (p-Cl-PhSe)2 and (F3CPhSe)2 were able to inhibit the cell growth, although the inhibition was considerably weaker than that by (PhSe)2, (PhTe)2 and (MeOPhSe)2. In Candida suspensions incubated in a medium containing serum as an inducer of germ tube formation, the presence of either (PhSe)2 or (MeOPhSe)2 at 10 μmol l−1 completely inhibited the number of cells which formed germ tubes. These results demonstrate the potential of organochalcogenide compounds to inhibit both C.

The link between Tregs and the ‘hygiene hypothesis’ is discussed in detail elsewhere in this workshop. In principle, stimulation of the T cell system via microbial-derived signals GPCR Compound Library clinical trial emanating principally from the GIT may be one route via which functionally mature Tregs are generated, and these cells may contribute to maintenance of homeostasis in peripheral tissues distal to the GIT. In early life, one source of such Tregs may be recent thymic emigrant (RTE) CD4+ T cells. Human in vitro studies from

our group and others [16,45,47], echoing earlier work in the mouse [48], have demonstrated that naive RTE which dominate the circulating CD4+ T cell compartment during infancy respond ‘non-specifically’ to peptides, leading to rapid activation and cytokine production which is usually terminated soon thereafter by apoptotic death. However, a subset of these RTE survive and potentially may thus enter the recirculating T cell compartment [16,47]. These survivors acquire Treg Ulixertinib price activity during the activation process [16]; this process may reflect events occurring in the lymphoid drainage of the GIT under the influence of microbial-derived antigens, providing a continuous ‘drip-feed’ of functionally activated Tregs. The de novo generation

and/or boosting of existing Treg activity by controlled microbial stimulation of the GIT is one of the aims of probiotic therapies which are being tested in many centres internationally, but there are few direct data available to confirm the efficient operation of this mechanism in humans. However, recent mouse data support the potential feasibility of this approach. In particular, gavage of mice with a bolus of live Lactobacillus reuteri increases numbers and functional activity of

Tregs in central lymphoid organs [49]. Moreover, if this is carried out in sensitized animals prior to aeroallergen challenge, ensuing lung eosinophilia and airways hyperresponsiveness is attenuated significantly and this effect can 2-hydroxyphytanoyl-CoA lyase be reproduced by adoptive transfer of Tregs harvested from spleens of L. reuteri-gavaged animals [49]. We have obtained similar findings in a rat atopic asthma model employing repeated feeding with a microbial extract containing multiple TLR ligands, and moreover we have observed that the attenuation of aeroallergen-induced airways inflammatory responses in prefed animals is associated with increased baseline numbers of Tregs in the airway mucosa (to be published). These latter findings suggest that one of the principle tenets of the ‘common mucosal immune system’ concept, notably that adaptive immune cell populations activated in the GIT mucosa will subsequently traffic preferentially to other mucosal sites, may be exploitable in relation to therapeutic control of allergy-induced lung inflammation.

This commonly results in direct sensitization against the partner, potentially making

him an unsuitable donor. HAR may also occur in blood group incompatible transplantation without desensitization. Preformed antibodies cause rejection by binding to HLA antigens expressed on the endothelium of vessels in the transplanted kidney, resulting in activation of the complement cascade with resultant thrombosis and infarction of the graft (reviewed in2). HAR can occur immediately upon reperfusion of AZD6244 price the donor kidney. This catastrophic outcome necessitates the immediate removal of the graft. Clearly avoiding HAR is desirable and crossmatching helps predict and hence prevent this.3 In brief, a crossmatch involves placing recipient serum (potentially containing donor-specific anti-HLA antibodies) onto donor lymphocytes (containing HLA antigens). A cytotoxic reaction (deemed ‘positive’) suggests the presence of preformed DSAbs. A more detailed description is provided later in this manuscript. A 44-year-old woman with end-stage renal failure secondary to reflux nephropathy is interested in a renal transplant and her husband has offered to be a donor. They are of the same blood group but are unmatched on tissue typing (0/6 HLA matches at the HLA-A, -B and -DR loci). They have a complement-dependent cytotoxicity (CDC) crossmatch performed as part of their initial assessment, which shows a positive result for both the T- and B-cell crossmatch (Table 1). Is it safe

to STK38 proceed? It is not safe to proceed in light of these crossmatch results but clarification steps are needed to better

understand buy PD0325901 the reason for the positive results. This could be a falsely positive result (technical issue) or there may be autoantibodies (against lymphocyte antigens) present in the recipient serum. Autoantibodies are generally IgM rather than IgG antibodies. To establish if autoantibodies are responsible for the result an auto-crossmatch should be performed. In this assay, recipient serum is crossmatched against recipient (rather than donor) lymphocytes. Second, the original crossmatch should be repeated with the addition of the agent Dithiothreitol (DTT). DTT reduces the disulfide bonds in IgM thereby preventing IgM antibodies from generating a positive result. IgM antibodies are generally regarded as having no pathological significance in transplantation.4–7 If a repeat crossmatch with DTT is negative then it may be safe to proceed with the transplant. An auto-crossmatch adds weight to this analysis by determining if the recipients are reacting against their own T or B cells in a similar way (Table 2). These results suggest that the reaction of the recipient to the donor is on the basis of autoantibodies. This means that the transplant could proceed using this pairing; however, before most live donor transplants and indeed cadaveric transplants more information is routinely available that aids in forming a more complete assessment of immunologic risk.

36–39 In the field of TCR gene transfer, this approach has been used to target viral-escape mutants occurring in chronic viral infections. Recently, Varela-Rohena et al.40 used phage display to generate affinity-matured TCRs specific for an HLA-class I-presented human immunodeficiency virus (HIV)-derived SL9 peptide epitope.

When variant α and β chains were combined, the affinities, as determined by surface plasmon resonance, were increased markedly, with one mutated TCR binding to the peptide–MHC complex with a half-life in excess of 2·5 hr. Following transduction of the mutated TCRs into CD8 T cells, antigen specificity was retained and the Ponatinib mouse TCR-transduced T cells produced a greater range of cytokines and increased Cisplatin chemical structure amounts of IL-2 in response to HIV-infected target cells compared with the CTL line from which the wild-type TCR was isolated. A number of concerns exist regarding the generation of TCRs with supraphysiological peptide–MHC complex affinities. It is likely that there is an affinity threshold for optimal TCR function. For

example, the serial triggering model suggests that a peptide–MHC complex molecule can consecutively interact with several TCRs, resulting in a signal amplification mechanism.41 This requires a balance between TCR/affinity and the on/off rate. Serial triggering is facilitated by a relatively fast off rate of the TCR-MHC/peptide interaction. It is conceivable that in vitro-selected TCR molecules, achieving affinities far above the affinity window of natural TCR repertoires, and markedly extended off rates, upset this balance and may fail to deliver appropriate signals required for T-cell activation and memory development in vivo. Furthermore, it has been reported that CD8 T cells transduced with the high-affinity TCRs show a lack of

peptide fine-specificity42 and as the affinity of a TCR is increased, the number of stimulatory peptides it can recognize also increases.43 There is therefore concern that these T cells will show cross-reactivity with the self-peptide–MHC complex. Interestingly, CD4 T cells transduced with the high-affinity TCRs continue to show peptide PIK3C2G specificity, and the increase in TCR affinity is accompanied by an increase in peptide recognition and T-cell avidity.44,45 This technique could therefore prove to be a valuable means to genetically modify CD4 T cells in order to acquire T-cell help in adoptive cancer T-cell therapies. A recently published method of increasing TCR affinity has arisen from data which suggest that increased glycosylation of T-cell-surface proteins is associated with an increased activation threshold, and vice versa. Kuball et al.46 demonstrated that deletion of defined N-glycosylation sites in the constant domains of the TCR-α and TCR-β chains increased the functional avidity of T cells transduced with these modified TCRs.

Post-mortem examination of the brains showed subtotal loss of cerebellar Purkinje cells in both cases. In the case with shorter survival time, areas with partial loss of cerebellar granule cells were observed, whereas in the case with longer survival time general and extensive loss of granule cells was found. Cells in other areas of the brain known to be sensitive to hypoxic injury were not affected. Selective loss of Purkinje

cells has previously been described in neuroleptic malignant syndrome and heatstroke, conditions that are characterized by hyperthermia. This this website suggests that hyperthermia may be a causative factor of brain damage in serotonin syndrome. This is the first report describing neuropathological findings in serotonin syndrome. “
“P. J. Kullar, D. M. Pearson, D. S. Malley, V. P. Collins and K. Ichimura (2010) Neuropathology and Applied Neurobiology36, 505–514 CpG island hypermethylation of the neurofibromatosis type 2 (NF2) gene is rare in sporadic vestibular schwannomas Aims: Loss of both wild-type copies of the neurofibromatosis type 2 (NF2) gene is found in both sporadic and neurofibromatosis

type 2-associated vestibular schwannomas (VS). Previous studies have identified a subset of VS with no loss or mutation of NF2. We hypothesized that methylation of NF2 resulting in gene silencing may play a role in such tumours. Methods: Forty sporadic VS were analysed by array comparative genomic hybridization using 1 Mb whole genome and chromosome 22 tile path arrays. The NF2 genes were sequenced and methylation of NF2 selleck chemicals examined by pyrosequencing.

Results: Monosomy 22 was the only recurrent change found. Twelve tumours had Cediranib (AZD2171) NF2 mutations. Eight tumours had complete loss of wild-type NF2, four had one mutated and one wild-type allele, 11 had only one wild-type allele and 17 showed no abnormalities. Methylation analysis showed low-level methylation in four tumours at a limited number of CpGs. No high-level methylation was found. Conclusions: This study shows that a significant proportion of sporadic VS (>40%) have unmethylated wild-type NF2 genes. This indicates that other mechanisms, yet to be identified, are operative in the oncogenesis of these VSs. “
“D. Gilden, R. Mahalingam, M. A. Nagel, S. Pugazhenthi and R. J. Cohrs (2011) Neuropathology and Applied Neurobiology37, 441–463 The neurobiology of varicella zoster virus infection Varicella zoster virus (VZV) is a neurotropic herpesvirus that infects nearly all humans. Primary infection usually causes chickenpox (varicella), after which virus becomes latent in cranial nerve ganglia, dorsal root ganglia and autonomic ganglia along the entire neuraxis. Although VZV cannot be isolated from human ganglia, nucleic acid hybridization and, later, polymerase chain reaction proved that VZV is latent in ganglia.

In addition to standard microbiological culture, we examined explanted suture and tissue specimens using CM to determine whether bacterial learn more biofilms were present. Specimens were prepared as described previously (Kathju et al., 2009a, b). Briefly, suture

and tissue recovered at surgery were placed in Hanks balanced salt solution (HBSS) and placed on wet ice, directly after removal. After rinsing in the HBSS (to remove unattached bacteria) and blotting on sterile paper, specimens were mounted on the bottom of a 35-mm Petri plate on partially solidified agar (Kathju et al., 2009a, b). Specimens were stained for viability assessment using Molecular Probes BacLight Live/Dead kit (Molecular Probes, Eugene, OR). The BacLight kit consists of two nucleic acid stains, Syto9 (green), which enters all bacteria, and propidium iodide (red), which can only enter bacteria with porous cell walls. Once inside the bacteria, the propidium iodide suppresses the Syto9 fluorescence so that live bacteria appear green, whereas dead or damaged cells appear red. In some cases, bacteria stain with both dyes

and appear yellow – these have been interpreted as live, but nonculturable. The nuclei of human cells also take up these nucleic acid stains, but rapidly turn red. They are readily distinguished from bacteria on the basis of size and morphology. In addition, these stains have been used to stain extracellular bacterial DNA Cytidine deaminase (eDNA), which is commonly found in the EPS and appears as a diffuse staining selleck surrounding the bacterial cells (Böckelmann et al., 2006; Thomas et al.,

2008). Fully hydrated specimens were then imaged by CM using a Leica DM RXE upright microscope attached to a TCS SP2 AOBS confocal system (Leica Microsystems, Exton, PA) using either a × 20 air objective or a × 63 long working distance water immersion objective. Live (green) and ‘dead’ (red) bacteria were imaged using 488 and 594 nm lasers; the suture and xenograft were imaged using reflected CM (blue) and bright-field microscopy (gray). Examination of one of the pieces of explanted Surgisis xenograft by CM showed heterogeneously distributed patches of live and dead bacteria and evidence of associated eDNA attached to the xenograft material (Fig. 2a). These organisms had a primarily coccal appearance, consistent with the solitary finding by culture of staphylococci. Interestingly, only one of the four specimens yielded a positive culture result, illustrating the inherent difficulty in detecting biofilm infections and making the case for multiple specimens to be sent for clinical culture, as well as the utility of using independent culture-free methods. Biofilms are commonly patchy on surfaces and this heterogeneity might partly explain the inconsistency in culture data. Examination of explanted suture material also showed evidence of attached and viable biofilm bacteria (Fig. 2c and d).

After euthanasia, pancreas were removed and fixed in phosphate-buffered formalin 10% (phosphate buffer pH = 7·2) for 24 h. The organs were conserved in alcohol 70% until histological processing and paraffin inclusion. Five-μm sections were cut and stained with haematoxylin and eosin (H&E). All islets on the slides were analysed and the following criteria

were employed to determine insulitis score: 0 = intact islet; 1 = peri-insulitis; 2 = moderate insulitis (< 50% mononuclear infiltration); and 3 = severe insulitis (more than 50% mononuclear infiltration). Spleen cells were cultured in RPMI-1640 medium supplemented AZD4547 molecular weight with 10% fetal bovine serum, 2 mM L-glutamine and 40 mg/l of gentamicin and then plated at 5 × 106 cells/ml in 48-well flat-bottomed culture plates (Nunc, Sigma-Aldrich) and stimulated with 10 μg/ml of recombinant heat shock protein 65-kDa (rhsp65). Cytokine levels were evaluated 48 h later by enzyme-linked immunosorbent assay (ELISA) in culture supernatants using interferon (IFN)-γ, interleukin (IL)-5 and IL-10 BD OptEIA Sets (Becton Dickinson, San Jose, CA, USA) and tumour necrosis factor (TNF)-α

Duoset (R&D Systems, Minneapolis, Nutlin 3 MN, USA). The assays were performed according to the manufacturer’s instructions. Spleen cells were collected, the red blood cells were lysed with Hanks’s buffer containing NH4Cl and the remaining cells were adjusted to 2·5 × 106 cells/100 μl. These cells were incubated with 0·5 μg of fluorescein isothiocianate (FITC) anti-mouse CD4 (clone GK1·5) and 0·25 μg of allophycocyanin (APC) anti-mouse Suplatast tosilate CD25 (clone PC61·5) for 20 min at room temperature. Staining for FoxP3 was then performed utilizing the phycoerythrin (PE) anti-mouse/rat FoxP3 Staining Set (eBioscience, San Diego, CA,

USA), according to the manufacturer’s instructions. After incubation, the cells were fixed in paraformaldehyde 1%. The cells were analysed by flow cytometry using FACSCalibur (Becton Dickinson) and BD CellQuest Pro software (Becton Dickinson, San Jose, CA). Results are presented as mean ± standard error of the mean (s.e.m.). For diabetes incidence, the χ2 test was used. In all other cases, one-way analysis of variance (anova) was used for parameters with normal distribution and the Kruskal–Wallis test for parameters with non-normal distribution. Dunn’s test was used when necessary. Significance level was P < 0·05. Statistical analysis was accomplished with SigmaStat for Windows version 3·5 (Systat Software Inc., Chicago, IL, USA). Weight variation, glycaemia and the score of mononuclear infiltration in the pancreas were analysed in mice immunized with BCG alone or with prime-boost (BCG followed by pVAXhsp65) before diabetes induction with STZ. As shown in Fig. 1a, although all the groups gained weight, BCG–STZ and BCG/DNAhsp65–STZ exhibited a smaller variation (3 and 1%, respectively) in comparison to the control group (9%).

This early transient downregulation of CD62L in IFNAR−/− P14 cells may be explained by the fact that surface CD62L is shed rapidly upon activation 21 without reduction of CD62L transcripts which would lead to CD62L re-expression

after initial surface shedding. Consistent with the MPEC phenotype, IFNAR−/− P14 cells failed to downregulate CD127 and to upregulate KLRG1 by day 6 of infection and were antigen-experienced since they uniformly Z-VAD-FMK solubility dmso expressed high levels of CD44 (data not shown). Similar results were obtained for WT and IFNAR−/− P14 cells in the draining LNs (Supporting Information Fig. 1A–D). Analysis of the relative SLEC and MPEC composition of the WT and IFNAR−/− P14 cell populations confirmed

that IFNAR−/− P14 cell differentiation was strongly biased toward the MPEC phenotype by day 6 post-infection, whereas WT P14 cells were distributed between an SLEC and MPEC phenotype (Fig. 2D). However, by day 60 post-infection, when memory P14 cells had formed, there was no longer a phenotypic difference Selleck Maraviroc between WT and IFNAR−/− P14 cells, supporting the notion that MPECs, giving rise to the memory population, were qualitatively not affected by the absence of type-I IFN signaling (Fig. 6C). Thus, IFNAR−/− P14 cells exhibited an augmented and accelerated MPEC phenotype (KLRG1low and CD127high) in sharp contrast to the pronounced effector phenotype (KLRG1high and CD127low) displayed by WT P14 cells (Fig. 2C). Taken together these data suggest that type-I Clomifene IFN signaling is an important factor that promotes transition of CD8+ T cells toward an SLEC phenotype. Based on the finding that type-I IFN signaling is a major regulator of

the expansion and survival of CD8+ T cells during LCMV infection 18–20, we aimed to exclude the possibility that IFNAR−/− P14 cells may initially form SLECs, which due to a lack of survival signals, are preferentially prone to undergo apoptosis. To this end, equal numbers of WT and IFNAR−/− P14 cells were CFSE labeled and transferred into WT hosts prior to co-infection with LCMV8.7 and VVG2 and their ability to divide and differentiate was analyzed in the spleen 2.5 days later. Both WT and IFNAR−/− P14 cells were initially activated and exhibited equal capacity to divide as shown by their CFSE dilution profile (Fig. 3A). Furthermore, by analyzing the phenotype of cells that have only undergone a few cell divisions (CFSE high) compared with cells that have undergone intermediate (CFSE mid) or high (CFSE low) numbers of cell divisions, we found that CD25 was significantly higher expressed on WT P14 cells in the CFSE high population compared with IFNAR−/− P14 cells, with these differences increasing with cell division. The opposite was observed for CD62L, where CD62L expression was higher on IFNAR−/− P14 cells compared with that of WT P14 cells in all stages of cell divisions (Fig. 3B).

To distinguish whether BMPs inhibited differentiation or if the reduced percentages of plasmablasts mainly were a result of reduced proliferation, naive and memory B cells were labeled with CFSE prior to culturing in the presence of CD40L/IL-21 with or without various BMPs.

This experimental design made it possible to follow differentiation per cell division. Of check details the memory B cells that had divided four times or more, only 6.5% of the BMP-6-treated cells compared with 21% of the BMP-7 treated cells had differentiated to CD38+ cells (Fig. 3C). This shows that BMP-6, more potently than BMP-7, inhibits plasma cell differentiation. These findings were further confirmed by division slicing 37 and subsequent calculations of percentage of cells in each cell division that had differentiated to CD27+CD38+ plasmablasts. Lumacaftor research buy This approach identified BMP-6 as the most potent suppressor of CD40L/IL-21-induced plasma cell differentiation, whereas BMP-2 and -4 had intermediate suppressive effects and BMP-7 had limited effects (Fig. 3D). CFSE tracking of cell division further

showed that the BMPs inhibited cell cycle progression as the percentage of cells that had divided four times or more was reduced in the BMP-treated cells (Fig. 3C and not shown). Taken together, the data shown suggest that BMP-6 inhibits Ig production mainly by inhibiting plasma cell differentiation, but also via suppression of proliferation. To further investigate plasma cell differentiation, we sorted memory B cells by FACS and cultured them

with CD40L/IL-21 in the presence or absence of BMP-6 and BMP-7 for 5 days and then analyzed the acquisition of the 17-DMAG (Alvespimycin) HCl plasma cell markers IRF-4, CD138 and XBP-1 by immunocytochemistry. Freshly purified memory B cells had no or low expression of IRF-4 and no detectable level of XBP-1 (Fig. 4). After 5 days of culture in the presence of CD40L/IL-21, 84% of cells expressed IRF-4 and 50% of them co-expressed XBP-1 (Fig. 4 and Supporting Information Fig. 4). CD138 was not detected (not shown), indicating that the differentiated cells were plasmablasts, and not fully mature plasma cells. In contrast, fewer cells were present when they had been cultured in the presence of BMP-6 or BMP-7 (compare Hoechst staining across the different culture conditions), and 44 and 36% of them expressed IRF-4 in the presence of BMP-6 and BMP-7 respectively. These data further support the finding that BMP-6 and BMP-7 block CD40L/IL-21-induced differentiation to plasmablasts (Fig. 4). We have previously shown that BMP receptors can be detected by flow cytometry 38. To characterize BMP receptor expression in naive and memory B cells, CD19+ cells from peripheral blood were stained with anti-BMP receptor Abs combined with detection of CD27 and CD20.

Therefore STAT6 not only is a key regulator of GATA-3 expression, but further contributes to Th2 commitment by preventing the acquisition

of the Th1, Th17 or Foxp3+ Treg cell phenotypes.51 It is now clear that not only STAT6, but also STAT5 plays an essential role in the initial steps of Th2 differentiation. Indeed, expression of constitutively active STAT5 is sufficient to induce IL-4 expression in cells lacking STAT6 or cultured under Th1 polarizing conditions,52 whereas IL-2 neutralization or STAT5 deletion prevents IL-4 secretion.53 Both STAT5 and GATA3, target the hypersensitivity enhancer region HSII located in the second intron of the il4 gene,52,54,55 and synergize to promote IL-4 secretion. Finally, STAT5 also regulates il4rα expression56 (Fig. 3). Ku-0059436 supplier This suggests that not only IL-2 but also other cytokines signalling through STAT5,

such as thymic stromal lymphopoietin, may be as important as IL-4 in driving Th2 development, as summarized in Table 1. Both SOCS1 and SOCS5 inhibit IL-4 signalling36,57 (Fig. 3); indeed, SOCS1-deficient T cells secrete increased levels of IL-4.29,31 SOCS5 also inhibits Th2 differentiation,39 but the relevance of this remains controversial because SOCS5-deficient mice do not have increased susceptibility to atopy, perhaps reflecting the close homology and likely redundancy between SOCS4 and SOCS5.37 Interestingly, SOCS3 and SOCS2 also regulate Th2 polarization, positively and negatively, respectively. Indeed, constitutive expression of SOCS3 in T cells confers increased susceptibility Luminespib in atopic models,33,39,58 while SOCS2-deficient mice develop exacerbated disease because of enhanced Th2 polarization.59 Surprisingly, neither SOCS3 nor SOCS2 seem to directly regulate IL-4 signalling. Instead, SOCS3 is a key regulator of IL-6-mediated or IL-23-mediated STAT360–62 and of IL-12-mediated STAT4 activation33 (Fig. 3), suggesting that SOCS3 may indirectly promote Th2 differentiation by preventing

the development of Th1 and Th17 cells. Similarly, SOCS2-deficient CD4+ T cells display reduced STAT3 activation and enhanced STAT5 phosphorylation and so SOCS2 probably inhibits Th2 differentiation Isotretinoin by inhibiting IL-2 signalling, while favouring the development of Th17 cells.59 Therefore, SOCS proteins control Th2 differentiation not only by inhibiting the activation of STAT6 and STAT5, but also by regulating the polarization of naive CD4+ T cells towards the other CD4+ lineages (Fig. 3). This is summarized in Table 2. T helper type 17 cells secrete high levels of IL-17A, IL-17F and IL-22 and play a key role at mucosal surfaces where they combat infection by extracellular bacteria. The Th17 cells are highly pro-inflammatory, and an alteration of the Th17 versus Treg cell balance is proposed as a potential mechanism that may induce autoimmunity.