It is possible that granzymes A and B show discordant expression in T regulatory cells [44]. The relative expression of perforin 1, the second element of perforin/granzyme

cytotoxic pathway, was not altered when compared to control group. Suppressors of cytokine signalling selleck inhibitor (SOCS) are involved in the balance of pro- and anti-inflammatory cytokine response. SOCS2 belongs to the FoxP3-dependent, Treg-specific molecules [45]. Our observations showed reduced mRNA expression of SOCS-2 and no change in SOCS-3 in Tregs separated from children with MS when compared to healthy subjects. There is some evidence that transcription factor FoxP3 can negatively regulate levels of SOCS-3 [46]. Interestingly, in contrast to our results, SOCS-2 expression was up-regulated in T cells separated

from peripheral blood of patients with rheumatoid arthritis and down-regulated in PBMC during anti-TNF-alpha treatment [47, 48]. The relation between master regulator of Tregs, FoxP3 and other transcription factors and cytokines at molecular level is complex and poorly understood. Some recent data demonstrated that STAT-1-activating cytokines IL-27 and IFN-γ influenced the FoxP3 expression induced by TGF-β [49]. The clinical significance of this finding is yet to be elucidated. Recently, it has been shown that IL-27 through the transcription factor c-Maf, IL-21 production and ICOS stimulation as an autocrine loop induce IL-10-producing T regulatory type 1 cells [50]. This co-operation seems learn more to explain Histone demethylase some of the complex relations between pro-/anti-inflammatory cytokines and transcription factors. Laboratory conditions similar to ours were used by Torcia et al. [21] in an experiment conducted in Fulani, an ethnic group with low susceptibility to malaria. The gene expression

analysis of Tregs (in this case CD4+CD25+ cells) showed very interesting results, some of which are in accordance to our observations. The expression of TGF-β1, CTLA-4 and SOCS2 in Tregs was lower in Fulani when compared to Mossi and European donors, IL-10 expression was not altered. However, these authors noted also lower FoxP3 mRNA levels in Fulani in comparison with other assessed populations. This suggests an early block in the Treg differentiation process driven by TGF-β. Furthermore, Fulani had lower TGF-β1 and no changes in IL-10 serum levels. This functional deficit of Tregs suggests the higher immune reactivity in Fulani, resulting in higher resistance to Plasmodium falciparum infection. The pathophysiological association between adipose tissue-derived cytokines and the promotion of atherosclerosis is well established but the role of T regulatory cells, which should hamper the self-destructive inflammation, remains to be determined (discussed in [51]). An important outcome of our study is that T regulatory cells in children with MS have some disturbances in gene expression which can contribute to immune imbalance in this group of patients.

Hantaviruses www.selleckchem.com/products/erastin.html are

transmitted to humans by inhalation of virus-containing aerosols that are derived from the excreta of hantavirus-infected rodents. These natural reservoir hosts remain asymptomatic, although they are persistently infected. In striking contrast, hantaviruses are eliminated in humans at the cost of severe symptoms such as pulmonary or renal failure. Currently, no suitable vaccines or therapeutics are available for prevention or treatment of human hantavirus infections [7, 8]. Hantaviruses are not directly cytopathic for infected cells, suggesting that the antiviral immune response itself causes hantavirus-associated syndromes [9, 10]. In accordance, hantaviruses trigger an unusually potent reaction of CD8+ T lymphocytes, that is devoid of regulatory T cells, and still detectable years after resolution [11-14]. Human CD8+ T cells are stimulated by HLA class I (HLA-I) molecules that present antigen-derived peptides. The latter are generated by proteasomes in the cytoplasm from newly synthesized viral proteins, translocated into the ER by TAP molecules, and loaded Panobinostat cell line onto HLA-I molecules before being shuttled to the cell surface. Moreover, uptake and processing of exogenous antigens for HLA-I presentation to CD8+ T cells is pivotal for the generation of antiviral immune responses [15]. This cross-presentation represents

an important function of DCs. Accordingly, most viruses have developed sophisticated strategies to subvert antigen presentation by BCKDHA HLA-I molecules [16]. The PRRs that recognize viral components

include endosomal and cytosolic receptors for RNA and DNA [17]. TLR3 and TLR4 have been implicated as sensors of hantavirus particles [18-20]. Recently, hantavirus-derived RNA was identified as a stimulus of retinoic acid inducible gene I (RIG-I), a cytoplasmic sensor of virus-derived RNA [21]. TLR ligation events result in recruitment of the adaptor molecule MyD88 with the exception of TLR3, which uses TIR domain containing adaptor inducing IFN-β (TRIF) for downstream signaling [22]. Hantavirus are known to potently induce HLA-I on various cell types including DCs [23], but how detection of hantaviral virions translates into HLA-I-restricted T-cell responses and which viral sensors are involved are as yet unknown. In this study, we elucidate in detail how hantaviruses modulate the HLA-I antigen presentation machinery. We used A549 cells, a human lung epithelial cell line, for analyzing the effect of Hantaan virus (HTNV) on the HLA-I antigen presentation machinery. In HTNV-infected A549 cells, productive infection was established (Fig. 1A) and intracellular flow cyto-metric analysis revealed enhanced HLA-I expression (Fig. 1B). Moreover, HLA-I and β2m surface expression was increased upon HTNV infection (Fig. 1C).

mansoni schistosomes, combined with a preliminary analysis of the S. mansoni Actin 1.1 (SmAct1.1) promoter sequence (23). Expression of luciferase driven by the SmAct 1.1 promoter was only transient. The authors suggest that the loss of expression over time was probably not because of the loss of plasmid, because transfected parasites that were no longer expressing the luciferase remained PCR positive for luciferase DNA for 8 weeks Palbociclib order following electroporation. This finding is similar to that reported by Yuan et al. (24). These results also indicated that the electroporation protocol described was either insufficient to deliver the transgene to the germline or that the transgene was not

integrated at high frequency to be able to be detected in transgenic F1 parasites. Most of the aforementioned strategies for the introduction of transgenes into parasitic helminths result in transient, nonheritable expression of the gene of interest. For many gene expression and functional studies, this may be sufficient; however, for other types of studies such as the investigation into cellular and molecular aspects of the host immune response to the parasite, heritable expression is required. Whilst techniques for transgenesis in the free-living nematode Caenorhabditis elegans have been established for decades, heritable transgene expression in parasitic worms is still in its

infancy, although significant inroads are being made into achieving this. It is unlikely that transfection with plasmid-based constructs, as Kinase Inhibitor Library mw described in many of the reports above, will result in chromosomal integration of transgenes. However, a way forward to achieve this aim is to use gene therapy-type approaches utilizing retroviruses (e.g. gamma retroviruses or lentiviruses),

retrotransposons or transposons, which enhance the likelihood of development of heritable, transgenic lines of schistosomes. This is particularly likely if germline cells can be targeted for transduction. In addition, retroviruses or transposons can be used to transfer gene cassettes for the production of siRNAs, thereby combining a powerful knock-down technology with an efficient delivery system offering the possibility for heritable RNAi targeting specific host cell genes (25,26). Together with colleagues, Sodium butyrate we have made the first attempts down this track and reported the use of retroviruses and transposons to transduce schistosomes (27,28). In Kines et al., we produced replication incompetent Moloney murine leukaemia virus (MMLV) virions that were pseudotyped with vesicular stomatitis virus glycoprotein (VSVG) carrying a luciferase reporter gene. Virions co-cultured with schistosomes interacted with the tegument of the worms and immunofluorescence studies indicated that the retroviral capsid and RNA genome were released within the surface cells.

Bcl6 can efficiently repress the expression of Blimp-1 and subsequent plasma cell differentiation ([8, 54, 61, 62], J. Alinikula, K.-P. Nera, S. Junttila and O. Lassila, unpublished

observations). The repression can occur directly by interfering with the function of Blimp-1-inducing STAT3 [62] and independently by binding to Blimp-1 intronic sequences [61, 63]. Additionally, Bcl6 may repress Blimp-1 via regulating the other repressors of Blimp-1, such as Bach2 (J. Alinikula, K.-P. Nera, S. Junttila and O. Lassila unpublished observations). Thus, the function of Bcl6 is to prevent the SAR245409 cell line premature differentiation of plasma cells to allow effective Ig SHM and CSR during the GC response (Fig. 3). In addition to inducing the activators of plasma cell differentiation, the repressors of plasma cell differentiation Pax5, MITF, Bach2 and Bcl6 [8, 28, 61, 62, 64, 65] need to be suppressed (Fig. 3). The downregulation of Pax5, a central factor for the commitment and maintenance of B cell phenotype [66], is crucial for the plasma cell differentiation [9]. Pax5 expression can efficiently prevent the differentiation of antibody-secreting plasma cells and the expression of Blimp-1 [9, 28, 67–69]. Pax5 also represses

the expression of Selleckchem AZD1152HQPA several genes associated with immunoglobulin secretion, such as Ig J-chain [70–72] and Xbp1 [8, 9, 35], and inhibits high-level transcription of Ig loci [73]. Inactivation of Pax5 gene in DT40 B cells induces plasma cell transcription programme and Ig secretion [8]. Conditional inactivation of Pax5 in mature B cells induces also a similar phenotype [28]. The downregulation of Pax5 is one of the initiating mechanisms of plasma cell differentiation in GCs. The evidence for this

comes from the experiments where Blimp-1 gene was engineered to harbour a GFP reporter gene [20]. This model was used to discover a population of GC cells called preplasmablasts that have downregulated the expression of Pax5 but not yet induced the expression of Blimp-1 [27] suggesting that B cell properties Oxalosuccinic acid are not lost only after the induction of Blimp-1 but rather precede the Blimp-1 expression. Pax5 can also directly repress the Blimp-1 expression [67]. In line with these results, inactivation of Pax5 in DT40 cells leads to spontaneous differentiation to plasma cells [8]. The mechanism for physiological suppression of Pax5 expression in GCs is however currently unknown. The Pax5-deficient DT40 cells have, however, also lost their Bcl6 expression [8] warranting the possibility that Pax5 deletion induces plasma cell differentiation via upregulation of Blimp-1 after losing Bcl6-mediated Blimp-1 repression. Indeed, Bcl6 expression in Pax5 deficient cells can repress Blimp-1 [8], but not vice versa: enforced Pax5 expression in Bcl6-deficient cells cannot repress Blimp-1 (J. Alinikula, K.-P. Nera, S. Junttila and O.

To increase the purity, the positively selected cell fraction containing the CD4+CD25+CD127dim/− regulatory T cells was separated over a second, new column. Depletion of non-CD4+ and CD127high cells was performed on an LD Column. The subsequent positive selection of CD4+CD25+CD127dim/− T cells was performed on two MS Columns. The purity of Treg separation was always greater

Seliciclib cell line than 90% as assessed in flow cytometer with monoclonal antibodies (CD4, CD25 and CD127). RNA extraction and cDNA synthesis.  Total RNA from T regulatory cells (CD4+CD25+CD127dim/−) was isolated and purified using Rneasy Mini Kit (Qiagen, Valencia, CA, USA) following the manufacturer’s protocol. RNA integrity was verified by 1.5% agarose gel electrophoresis/ethidium bromide staining and OD260/280 absorption ratio >1.95. One microgram of total RNA was used to prepare cDNA. cDNA synthesis was performed using SuperScript™ First-Strand Synthesis System for RT-PCR (Invitrogen, Carlsbad, CA, USA) according to the manufacturer’s instructions in the MJ Research Thermal Cycler (MJ Research, Model PTC-200; Watertown, MA, USA). Real-Time PCR.  The following

genes were assessed: (1) cytokines and H 89 solubility dmso chemokines: IL-2, IL-10 (and its receptor α), TGF-β1 (and its receptors 1 and 2), IL-12A, IL-17A, IL-21, IL-23, IL-27, EBI3, IL-8 receptor α, CCL22, interferon (IFN)-γ, tumour necrosis factor (TNF)-α; (2) critical Treg molecules: OX40, 4-1BB, ICOS, GITR, CTLA-4, perforin-1, granzyme A and (3) transcription factors: FoxP3, STAT1, STAT3, SOCS2, SOCS3, SMAD3 and T-box 21. The levels of transcripts were measured by real-time PCR using human genes QuantiTect Hs_IL7R_1_SG

Assay (Qiagen) and QuantiTect Hs_GAPDH Assay (Qiagen) as a normalizer. Real-Time PCR was performed in duplicate in 20 μl using mafosfamide the QuantiTect SYBR Green PCR Master Mix (Qiagen) following the manufacturer’s instructions and carried out in the Chromo4 Real-Time PCR Detector (BIO-RAD, Hercules, CA, USA). The thermal cycling conditions included an initial activation step at 95 °C for 15 min, followed by 40 cycles of denaturation, annealing and amplification (94 °C for 15 s, 55 °C for 30 s, 72 °C for 30 s). At the end of the amplification phase, a melting curve analysis was carried out on the product formed. The fluorescent data collection was performed during the annealing step. A standard curve construction was generated by using a serial of four dilutions of cDNA of the control group sample in reaction with the house-keeping gene, GAPDH. Based on these curves, the levels of total chosen gene transcripts were calculated after its normalization to GAPDH. The value of CT was determined by the first cycle number at which fluorescence was greater than the set threshold value. To calculate our data, according to Livak and Schmittgen [15], we used the comparative CT method for relative quantification i.e. 2−ΔΔCT method. Statistical analysis.

Comparative microarray analysis revealed an additional set of genes that were significantly upregulated in E10.5 TLR2+ CD11b+ macrophages. This analysis, together with our genetic, microscopic, and

biochemical evidence, showed that embryonic phagocytes express protein machinery that is essential for the recycling of cellular iron and that this expression can be regulated by TLR engagement in a MyD88-dependent manner, leading to typical inflammatory M1 responses. These results characterize learn more the utility of TLRs as suitable markers for early embryonic phagocytes as well as molecular triggers of cellular responses, the latter being demonstrated by the involvement of TLRs in an inflammation-mediated regulation of embryonic homeostasis via iron metabolism. “
“Synthetic oligonucleotides

(ODN) expressing CpG motifs mimic the ability of bacterial DNA to trigger the innate immune system via TLR9. Plasmacytoid dendritic cells (pDCs) make a critical contribution to the ensuing immune response. This work examines the induction Vismodegib datasheet of antiviral (IFN-β) and pro-inflammatory (IL-6) cytokines by CpG-stimulated human pDCs and the human CAL-1 pDC cell line. Results show that interferon regulatory factor-5 (IRF-5) and NF-κB p50 are key co-regulators of IFN-β and IL-6 expression following TLR9-mediated activation of human pDCs. The nuclear accumulation of IRF-1 was also observed, but this was a late event that was dependant on type 1 IFN and unrelated to the initiation of gene expression. IRF-8 was identified as a novel negative regulator of gene activation in CpG-stimulated pDCs. As variants of IRF-5 and IRF-8 were recently found to correlate with susceptibility to certain autoimmune diseases, these findings are relevant to our understanding of the pharmacologic effects of “K” ODN and the role of TLR9 ligation under physiologic,

pathologic, and therapeutic conditions. Cells of the immune system utilize TLR to sense ligands uniquely expressed by pathogenic microorganisms. Human plasmacytoid dendritic cells (pDCs) use TLR9 to detect Glutamate dehydrogenase the unmethylated CpG motifs present at high frequency in bacterial DNA [1-3]. Synthetic oligonucleotides (ODN) encoding unmethylated CpG motifs mimic the effect of bacterial DNA and trigger pDC activation. Several structurally distinct classes of CpG ODN have been described. Those of the “K” class (also referred to as “B” class) are characterized by their ability to stimulate human pDCs to secrete pro-inflammatory cytokines such as IL-6 and TNF-α. Clinical trials of “K” ODN show promise for the treatment of cancer, allergy, and infectious disease [4, 5]. Identifying the signaling pathways triggered when human pDCs are stimulated by “K” ODN is, thus, of clinical relevance. pDCs are a major source of type I IFNs and various pro-inflammatory cytokines [6, 7].

In this study, we address the question: Ivacaftor molecular weight can Ab targeting the high affinity FCR engineered to express CTL epitopes stimulate high-avidity CTL

responses that are capable of efficient anti-tumor activity? We have previously shown that Ab–DNA vaccines engineered to express CTL epitopes can stimulate high-frequency responses to self and foreign epitopes but it was unclear if these were of high avidity 26. Initially a DNA vaccine incorporating the H-2Kb OVA epitope, SIINFEKL, within a human IgG1 molecule was screened for stimulation of high-avidity CTL responses. The SIINFEKL epitope OVA was grafted into CDRH2 region alongside an I-Ab restricted CD4 helper epitope from Hepatitis B (HepB) surface Ag. C57BL/6 mice immunized with this DNA construct demonstrated high-frequency epitope-specific responses compared to a control irrelevant peptide (p<0.0001) (Fig. 1B). It was next assessed if encoding an epitope within an Ab–DNA vaccine could break tolerance to a self Ag. An epitope from the melanoma Ag tyrosinase related

protein 2 (TRP2) was engineered into a human IgG1 Ab alongside the HepB CD4 epitope. Immunized C57BL/6 mice also demonstrated high-frequency TRP2-specific responses, although these were lower than OVA-specific responses (p<0.0001) (Fig. 1C). The ELISPOT assays in this study use total splenocyte CX-4945 clinical trial populations and it is possible that other IFN-γ producing cells reside within this population. To address this, CD8+ cells were depleted prior to use in the ELISPOT assay. Depletion of the CD8+ cells eliminates the TRP2-specific response but has no effect upon the HepB helper peptide-specific response (Fig. 1D). To determine if there was any advantage in immunizing with Ab–DNA vaccine as compared to simple peptide immunization, T-cell responses to OVA/HepB

or TRP2/HepB human IgG1 DNA vaccines were compared to vaccination with HepB/OVA or TRP2/HepB http://www.selleck.co.jp/products/AG-014699.html linked peptides. Mice immunized with peptide show significantly lower frequency responses compared to human IgG1 DNA immunized mice (p<0.0001 and p=0.003, respectively) (Fig. 1e). Functional avidity of CD8 responses has been shown to be important in the induction of anti-tumor immunity. Analysis of the functional avidity revealed that responses induced in human IgG1 DNA immunized mice were over 100-fold higher compared to peptide immunized mice for both OVA and TRP2 epitopes (p<0.0001 and p=0.0009, respectively) (Fig. 2A and B). OVA human IgG1 DNA shows avidity of 1×10−11 M compared to OVA peptide at 1.3×10−9 M. TRP2 human IgG1 DNA demonstrates an average avidity of 6×10−12 M compared to TRP2 peptide at 1.7×10−9 M.

These five mutations are associated with 70–90% of all ethambutol-resistant

isolates (Johnson et al., 2006). The early and rapid detection of multidrug resistance is essential for efficient treatment and control of M. tuberculosis. The culture-based methods for detection of M. tuberculosis infection and PXD101 supplier drug susceptibility testing (DST) usually take more than 1 month due to the slow growth of this bacterium. The use of molecular methods for the identification of mutations in the resistance genes may offer the means for rapid screening of the drug resistance among the M. tuberculosis isolates and initiation of early treatment. In Jordan, although the incidence rate of tuberculosis declined in 1990–2010, the number of MDR-TB reported cases increased (WHO, 2010). In the present study, three Talazoparib concentration different allele-specific PCRs (AS-PCR) that were previously optimized and validated were carried out directly with purified DNA to detect mutations in several codons in the rpoB, katG, and embB genes of M. tuberculosis isolates (Mokrousov et al., 2002a, b, 2003). The AS-PCR primers are used to amplify and discriminate between two alleles of a gene simultaneously. One benefit of AS-PCR is that it combines the amplification with detection events

without the necessity for additional probes or enzymes. A total of 100 M. tuberculosis-resistant strains were selected randomly from sputum cultures of tuberculosis patients obtained from the stock cultures of the Directorate of Chest Diseases and Foreigners Health (referred to as the TB Center for short), Ministry of Health in Amman, Jordan. Neratinib ic50 These isolates were recovered from sputum specimens of adult patients diagnosed with pulmonary tuberculosis who were referred to the TB Center from eight cities in Jordan in 2007. Multiple isolates from the same patient were avoided. Species identification of the isolates was confirmed in the TB Center using a combination of standard microbiological tests: colony morphology, acid-fast staining, and conventional biochemical tests. The study was approved by the University Internal Review Board. The simplified version of the indirect proportion method was performed in the TB Center on Löwenstein–Jensen

medium against isoniazid, rifampicin, and ethambutol, at 0.2, 40, and 2 μg mL–1, respectively, according to standard procedures (Canetti et al., 1969). Each M. tuberculosis isolate was inactivated by a touch swab placed in an Eppendorf tube containing 500 μL of 1 × Tris-EDTA buffer (pH 8.0), and tubes were incubated at 80 °C in a water bath for 20 min. The M. tuberculosis H37Rv, and a collection of five to eight randomly selected clinical isolates that were susceptible to all the three test drugs were also included as reference strains in the study. DNA was extracted from the M. tuberculosis isolates using standard protocols as described previously (Van Soolingen et al., 1991). All PCR amplifications were carried out in GenAmp 9700 (Perkin Elmer). Each run of AS-PCR included M.

In the common form, there was no difference

between the two, while in the pure form, Japanese cases were usually of young onset with parkinsonism as the chief symptom and Euro-American cases were of older onset with progressive dementia as the chief symptom, similar to the common form. Around that time, the term “senile dementia of Lewy body type” was proposed by Perry et al.,13 and the term “Lewy body variant of Alzheimer’s disease by Hansen et al.14 in 1990. In 1995, the first International buy EPZ015666 Workshop7 was held in Newcastle-upon-Tyne, UK. Then, the term “dementia with Lewy bodies” (DLB) was proposed, and the clinical and pathological diagnostic criteria (Consortium on Dementia with Lewey Bodies guidelines)8 were published in Neurology in 1996. In 1996, we proposed the cerebral type of Lewy body disease,15 in which progressive dementia without parkinsonism was the main symptom, and cortical Lewy bodies were marked in the cerebral cortex, but only rare Lewy bodies were present in the brain stem. The presence of the cerebral type means that Lewy bodies could occur first in the cerebral cortex and later develop in the brain stem. As above-mentioned,

we proposed the term Lewy body disease in 1980,11 and since then, we have insisted that DLB(D), PD, and Parkinson’s disease with dementia this website (PDD) should be understood within the spectrum of Lewy body disease.16 This insistence has been recently accepted by the International Workshop and the International Working Group on DLB and PDD in 200517 and in 2006,18 respectively. In 1997, two very important findings

were reported. Polymeropoulas et al.19 reported the mutation of the alpha-synuclein gene in familial PD, and Spillantini et al.20 reported alpha-synuclein in Lewy bodies. Since then, alpha-synuclein has received attention in neuropathological and molecular biological studies. Our alpha-synuclein immunohistochemical examination of materials from the first DLBD case disclosed much more marked Lewy pathology in the cerebral cortex than we had expected. Only this Lewy pathology could explain the profound dementia in this case. In addition, Dichloromethane dehalogenase this case also had both PD and AD. Therefore, the case is now diagnosed as having a common form9 (especially AD form10) of DLB(D). The authors thank Mrs Chie Haga, and Dr Haruhiko Akiyama, Tokyo Institute of Pschiatry for technical assistance. “
“Heterozygous LIS1 mutations are the most common cause of human lissencephaly, a human neuronal migration defect, and DCX mutations are the most common cause of X-linked lissencephaly. Lissencephaly is characterized by a smooth cerebral surface, thick cortex and dilated lateral ventricles associated with mental retardation and seizures due to defective neuronal migration. Lissencephaly due to the heterozygous loss of the gene LIS1 is a good example of a haploinsufficiency disorder.

The aim of this study was to investigate if PMNs from AAV patients are stimulated more readily by ANCA BGJ398 compared with

PMNs from healthy controls (HCs). Differences in ANCA characteristics that can account for different stimulation potential were also studied. PMNs from five AAV patients and five HCs were stimulated with 10 different immunoglobulins (Ig)Gs, purified from PR3–ANCA-positive patients, and ROS production, degranulation and neutrophil extracellular trap (NET) formation was measured. ANCA levels, affinity and clinical data of the AAV donors were recorded. The results show that PMNs from AAV patients produce more intracellular ROS (P = 0·019), but degranulate to a similar extent as PMNs from HCs. ROS production correlated with NET formation. Factors that may influence the ability of ANCA to activate PMNs include affinity and specificity for

N-terminal epitopes. In conclusion, our results indicate that PMNs from AAV patients in remission behave quite similarly to HC PMNs, with the exception of a greater intracellular Selleckchem GSK1120212 ROS production. This could contribute to more extensive NET formation and thus an increased exposure of the ANCA autoantigens to the immune system. “
“In the thymus, in order to become MHC-restricted self-tolerant T cells, developing thymocytes need to interact with cortical and medullary thymic epithelial cells (TECs). Although the presence of a common bipotent progenitor for these functionally and structurally distinct epithelial subsets has been clearly established, the initial developmental stages of these bipotent cells have not been well characterized.

In this issue of the European Journal of Immunology, Baik et al. [Eur. J. Immunol. 2013.43: 589–594] focus on the phenotypical changes Wilson disease protein of the early bipotent populations and show how the cortical and medullary markers are sequentially acquired during TEC development. These findings argue against a binary model in which both cortical and medullary lineages diverge simultaneously from lineage-negative TEC progenitors and highlight an unexpected overlap in the phenotypic properties of these bipotent TECs with their lineage-restricted counterparts. The essential function of the thymus is to generate and select new T cells with functional and self-tolerant TCRs for proper adaptive immune responses. During embryogenesis, the thymus, together with parathyroid glands, originates from the third embryonic pharyngeal pouch, and in the mouse, starts to form around embryonic day E10 and E11 of gestation.