We consistently observed constitutive expression of TLT-2 in LN C

We consistently observed constitutive expression of TLT-2 in LN CD8+ T cells from naive mice, and its expression was comparable in RLN CD8+ T cells from tumour-bearing Selleckchem beta-catenin inhibitor mice. Here, we examined TLT-2 expression in TIL for the first time. We found a marked lymphocyte infiltration within the B7-H3/SCCVII tumour mass, indicating active anti-tumour immune responses in the B7-H3+ tumour sites. Surprisingly, the majority of CD8+ TIL in the B7-H3/SCCVII-inoculated mice

lost TLT-2 expression, and the cells expressing activation marker down-regulated TLT-2 expression. These findings suggest that activation signals to CD8+ T cells induce down-regulation of TLT-2. Although we tried to detect TLT-2 expression by immunofluorescence histostaining, TLT-2 expression was undetectable so we could not examine the distribution of TLT-2+ versus TLT-2− CD8 TIL in the tissues. We also found that TGF-β, which is often secreted from solid tumour cells like squamous cell carcinomas or tumour-associated cells, down-regulated TLT-2 expression. It is therefore possible that some tumour-related environmental factor(s) may have caused

TLT-2 down-regulation. TLT-2 down-regulation occurred at the local tumour sites and this may have contributed to the limited efficacy of B7-H3-transduced tumours. Our results from the TLT-2-transduced CD8+ T-cell study suggest that the TLT-2 expression level is more critical than that of B7-H3 to deciding whether there is a contribution of the B7-H3–TLT-2 pathway. Over-expression of B7-H3 is no longer required selleck compound when sufficient TLT-2 expression is provided on the surface of CD8+ T cells (Fig. 6d). In

contrast to broad and abundant B7-H3 expression, TLT-2 expression levels in T cells are tightly regulated. Additional approaches for preventing TLT-2 down-regulation or enhancing TLT-2 expression at tumour sites may be needed. We performed experiments to block the B7-H3–TLT-2 pathway, using anti-B7-H3 and anti-TLT-2 mAbs, to confirm the functional contribution of B7-H3 and TLT-2 in B7-H3-introduced tumour-mediated immunity. Unfortunately, mafosfamide there was no effect on the tumour regression induced by B7-H3-introduced tumours that expressed high levels of B7-H3. Interestingly, growth of the parental tumour, which expressed endogenously low levels of B7-H3, was accelerated by treatment with either anti-B7-H3 or anti-TLT-2 mAb. This suggests the immunoenhancing effects of the B7-H3–TLT-2 pathway in tumour immunity against parental tumours. We have previously attempted and failed to reverse the enhanced responses induced by B7-H3- or TLT-2-transduced cells using the same anti-B7-H3 and TLT-2 mAbs in vitro, although these mAbs could inhibit B7-H3 immunoglobulin binding, assessed by flow cytometry, and the functional endogenous TLT-2 and B7-H3 interaction in contact hypersensitivity in vivo.28 The low affinity of our blocking mAbs may explain the failure.

14,15 Yet, whereas all of these studies clearly confer on CD8+ T

14,15 Yet, whereas all of these studies clearly confer on CD8+ T cells an important role in intestinal inflammation, none of these studies has been focused on the induction of truly CD8+ regulatory

T cells that express forkhead box P3 (Foxp3). In a previous study we demonstrated that the intestinal expression of a self-antigen leads to the induction of antigen-specific CD8+ Foxp3+ T cells in vivo.16 Furthermore, we have demonstrated that in vitro stimulation of antigen-specific CD8+ T cells in the presence of transforming growth factor-β (TGF-β) and retinoic acid (RA) induced a robust population of CD8+ Foxp3+ regulatory T cells.17 As the intestine is characterized by abundant production of TGF-β and RA it might therefore be prone to the Small Molecule Compound Library induction of Foxp3+ regulatory T cells. As these cells might play an as yet underestimated role in the maintenance of intestinal homeostasis, we have investigated CD8+ Foxp3+ T cells generated by TGF-β and RA by analysing the function and phenotype in humans and mice. Our study shows that TGF-β/RA-converted CD8+ Foxp3+ T cells share all the major features of conventional CD4+

regulatory T cells, i.e. suppressive function in vitro. Furthermore, these subsets of regulatory T cells also resemble each other at the molecular level as determined by gene expression studies. The fact that this conversion by TGF-β and RA also works with human CD8+ T cells Roxadustat ic50 is of particular interest because we demonstrate in this study that the frequency of CD8+ Foxp3+ T cells is reduced in the peripheral blood of patients with intestinal inflammation. Hence, our study illustrates a previously unappreciated critical role of CD8+ Foxp3+ T cells in controlling potentially dangerous T cells. Foxp3/GFP mice express both the Foxp3 and green fluorescent protein (GFP) under the endogenous regulatory sequence of the Foxp3 locus and were obtained from the Charles River Laboratories (Sulzfeld,

Germany). BALB/c mice and C57BL/6 mice were obtained from Harlan Laboratories (Harlan Winkelmann GmbH, Borchen, Germany). Granzyme B (GzmB) -deficient C57BL/6 mice were kindly provided by Prof. Dr U. Dittmer (Department of Virology, University Duisburg-Essen). Blood samples Methisazone were obtained from 12 patients (five men, seven women; age range, 32–72 years) with active ulcerative colitis (UC) and from 18 healthy blood donors (eight men, ten women; age range, 22–87 years), who were used as control group. To assess disease activity, the clinical activity index (CAI) according to Rachmilewitz’s criteria and the ulcerative colitis disease activity index (UCDAI) according to Sutherland’s criteria, including a grading of clinical and endoscopic signs, were determined. Patients were classified as having acute UC with a CAI > 4. Peripheral blood mononuclear cells were isolated from heparin-treated blood by Bicoll density gradient centrifugation (Biochrom AG, Berlin, Germany).

Seven successive questions, numbered from 1 to 7 in the IPSS, wer

Seven successive questions, numbered from 1 to 7 in the IPSS, were divided into two groups. These consisted of questions 1, 3, 5, and 6 and questions 2, 4, and 7, that represented voiding and storage symptoms, respectively.

If the mean voiding symptom score, defined as the summation score of questions 1, 3, 5, and 6, divided by 4 ([sum of scores for questions 1, 3, 5, and 6]/4) was greater than the mean storage symptom score ([sum of scores for questions 2, 4, and CTLA-4 antibody inhibitor 7]/3), then the patients were included in the voiding LUTS group. Otherwise, they were considered to be in the storage LUTS group.[16] The patients’ medical histories were obtained, and physical examinations, including neurological examination, were performed. Complete blood count, prostate specific antigen (PSA), glucose, creatinine, and liver enzyme analyses, urinalysis, and uroflowmetry were performed on the patients as well. Prostate volume and post-micturitional volume were assessed with ultrasonography. Ultrasound-guided needle biopsies were performed in cases where there was a suspected

malignancy (e.g., elevation of PSA > 4, suspicion of malignancy on digital rectal examination). Exclusion criteria were as follows: (i) any condition that can disrupt brainstem reflex, such as cranial nerve lesions, cerebrovascular disease, disease associated with neuropathy, AZD1208 in vitro or being treated with drugs recognized as potentially causing neuropathy, (ii) abnormal findings in the neurological examination, (iii) abnormal findings on brain MRI scan (iv) medical treatment for ID-8 LUTS, (v) signs of cancer of the urinary tract, (vi) history of pelvic surgery, (vii) any alcohol usage, or (viii) any abnormality determined by the blood and urine analysis listed above. Of the 32 patients, 16 had mean storage symptom scores that were higher than their mean voiding symptom scores and peak flow rates higher than 15 mL/sec. These patients had frequency and nocturia that was

greater than 7 and 1, respectively. All of the patients in the storage LUTS group had urge incontinence. The other 16 patients had mean voiding symptom scores that were higher than their mean storage symptom scores and peak flow rates lower than 10 mL/sec. All of the patients had previously provided a urination pattern detailing the time and volume of each urination over at least 3 days. The afferent limb of the blink reflex travels in the ophthalmic division of the trigeminal nerve, known as the supraorbital nerve. The supraorbital nerve can be stimulated by surface electrodes during EMG. The facial nerve subserves the efferent limb and contracts the orbicularis occuli muscle (Fig. 1). The blink reflex responses from the inferior portion of both orbicularis oculi muscles may be recorded simultaneously, through surface electrodes, during EMG. While the EMG was being recorded, patients were supine on a bed, in a warm room, with their eyes slightly closed.

Postoperatively, the patient was able to consume a normal diet wi

Postoperatively, the patient was able to consume a normal diet without difficulty or aspiration and displayed good speech function. No donor site morbidity, e.g., herniation or bulging, was observed, and the patient was able to perform their normal daily activities. DIEP flaps provide a pliable skin paddle, an adequate

amount of adipose tissue, and reduced donor site morbidity, even in children. We did not have any difficulty harvesting the DIEP flap or with the microvascular anastomosis. We consider DIEP free flaps to be the ideal option for pediatric tongue reconstruction. © 2013 Wiley Periodicals, Inc. Microsurgery 33:487–490, DAPT cell line 2013. “
“A Mathes and Nahai type III muscle, such as the rectus abdominis muscle, can be utilized to cover two separate wounds simultaneously utilizing its dual blood supply thereby minimizing Selleck Caspase inhibitor donor site morbidity and operative time. We report a case for treatment of bilateral Gustillo type IIIB lower extremity injuries treated with a single rectus abdominis muscle split into two free flaps, with one based on the deep inferior epigastric vessels and one on the superior epigastric vessels to cover the contralateral wound. In our patient, both lower extremity wounds were covered with muscle flaps from the same donor site in a single operation, salvaging both limbs with progression to unassisted ambulatory status. We show

in this case report that the utilization of the vascular anatomy of the rectus muscle allows for division of the flap into two flaps, permitting preservation of the contralateral abdominal wall integrity and coverage of two wounds with a single muscle. © 2013 Wiley

Periodicals, Inc. Microsurgery 34:54–57, 2014. With the improved survival of polytrauma patients, Phospholipase D1 the rise in concurrent open wounds is becoming increasingly common. Despite technical advances in free tissue transfer, donor site morbidity continues to be problematic for patients following lower extremity reconstruction. Often, these patients are young and will contend with the complications of donor site morbidity for many decades. As a consequence, the selection of donor sites is becoming a critical decision. Integration of multiple factors of patient age, aesthetics, and the conservation of upper body strength for assistance with ambulation and activities of daily living as well as the volume of soft tissue needed for transfer is critical when approaching a case of bilateral Gustillo IIIB injuries. The rectus abdominis free flap, first described by Pennington, has been long recognized as an ideal choice for lower extremity reconstruction, and indeed represents a workhorse flap for many microsurgeons.[1] Taylor et al. reported the successful use of the inferior third of the rectus muscle in their early case series of seven patients, noting that a small segmental component of the flap was more than sufficient to cover the soft tissue defect in nearly all cases.

Whole body imaging of adoptively transferred T cells using magnet

Whole body imaging of adoptively transferred T cells using magnetic resonance imaging, single photon emission computed tomography selleck products and positron emission tomography techniques, with a focus on regulatory T cells. Clinical and Experimental Immunology 2013, 172: 169–77. Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic synovial inflammation, leading to destruction of joint cartilage and bone. Although the precise aetiology remains to be established, it is thought that RA results from a breach in immune tolerance. T cell responses to several (joint-associated) autoantigens, including ‘altered self’ citrullinated peptides, can be detected in a

proportion of RA patients [1-8], and the function of peripheral blood regulatory T cells (Tregs) is impaired in RA patients with active disease [9]. Immunosuppressive drugs (including biological drugs) can relieve disease symptoms effectively, but none of the currently see more available treatments provide a cure, i.e. a long-lasting and drug-free remission of RA [10, 11]. Moreover, these drugs can increase the risk of serious infections [12-14]. The ‘holy grail’ of the immunotherapy field is

to develop a therapy that targets and rectifies the pathological autoimmune response specifically and effectively, while leaving protective immunity intact. A new immunotherapeutic approach aims to achieve restoration of immune tolerance by treatment with autologous dendritic cells (DC) with tolerogenic function [tolerogenic DC (tolDC)]. Here we review recent progress in this field. Destructive autoimmunity is normally prevented through active silencing of autoreactive T cells, a process in which Etofibrate DC play a central role. In the thymus self-reactive T cells are deleted, but this process of ‘central tolerance’ has limitations and some autoreactive T cells escape to peripheral tissues. Here they are kept under control by a variety of mechanisms, termed collectively ‘peripheral tolerance’. When tolerance mechanisms

break down, autoreactive T cells can acquire proinflammatory properties [e.g. become T helper type 1 (Th1) or Th17 cells] and mount an attack on the body’s own tissues, causing an autoinflammatory, destructive immune response [15]. For example, a shift from a tolerogenic to a proinflammatory T cell response in RA has been reported by van Bilsen et al. [3]. They detected CD4+ T cells specific for the autoantigen human cartilage gp39 (HCgp39) in both healthy individuals and RA patients. However, HCgp39-reactive T cells from healthy individuals exhibited a regulatory phenotype [interleukin (IL)-10 production, forkhead box protein 3 (FoxP3) expression, capability to suppress T cell responses], whereas HCgp39-reactive T cells from RA patients produced the proinflammatory cytokine interferon (IFN)-γ and lacked suppressive activity.

4%) directed antifungal therapy Mostly, systemic antifungal ther

4%) directed antifungal therapy. Mostly, systemic antifungal therapy was administered empirically or pre-emptively. Twenty-nine per cent of cases receiving systemic antifungal treatment met the international consensus criteria of mostly possible IFI, whereas 71% did not. Proven invasive fungal infections

were rare. “
“Candidaemia is associated with high mortality. selleckchem Despite the fact that Candida species account for close to 10% of all nosocomial bloodstream infections, relatively few studies have investigated the management of candidaemia in hospitals. Our objective was to find out how candidaemia is managed in hospitals. Data relating to all episodes of candidaemia for the year 2008 were retrospectively collected Selleckchem Tyrosine Kinase Inhibitor Library in five centres in Scotland and Wales. A total of 96 candidaemic episodes were recorded in the year 2008, yielding 103 isolates of Candida. Fifty candidaemic episodes were caused by Candida albicans. Fluconazole was the most common agent prescribed for the treatment of candidaemia. There was great variation in the prescribed dose of fluconazole.

Forty per cent of patients who survived received <2 weeks of systemic antifungal therapy. Central venous catheters (CVC) were removed in 57% of patients. CVC removal was not associated with better survival. The overall mortality was 40.4%. Management of candidaemia varies between the UK centres and is often inadequate. There is need to have consensus on the dosages of antifungal agents and the duration of therapy. The current guidance on removal of CVC in all cases of candidaemia should be reviewed. "
“Although photodynamic therapy (PDT) has shown great promise for the inactivation of Candida species, its effectiveness against azole-resistant

pathogens remains poorly documented. This in vitro study describes the association of Photogem® (Photogem, Moscow, Russia) with LED (light emitting diode) light for the photoinactivation of fluconazole-resistant (FR) and American Type Culture Collection (ATCC) strains of Candida albicans and Candida glabrata. Suspensions of each Candida strain were treated with five Photogem® concentrations and exposed to four LED light fluences (14, 24, 34 or 50 min of illumination). Celecoxib After incubation (48 h at 37 °C), colonies were counted (CFU ml−1). Single-species biofilms were generated on cellulose membrane filters, treated with 25.0 mg l−1 of Photogem® and illuminated at 37.5 J cm−2. The biofilms were then disrupted and the viable yeast cells present were determined. Planktonic suspensions of FR strains were effectively killed after PDT. It was observed that the fungicidal effect of PDT was strain-dependent. Significant decreases in biofilm viability were observed for three strains of C. albicans and for two strains of C. glabrata.

[37, 40, 42] Superficial infections can occur in patients sufferi

[37, 40, 42] Superficial infections can occur in patients suffering from an immunosuppressive disorder, such as leukaemia or HIV, but also in premature infants and apparently healthy adult persons.[42, 45-52] They are characterised by rapidly developing extensive tissue necrosis leading to purple to black discolouration of the skin.[45, 53] In individual cases R428 mouse involvement

of deeper tissue, leading to necrotising fasciitis and cellulitis, has also been reported.[40, 46, 54] In the most severe cases, cutaneous infections can progress to disseminated disease, especially in immunocompromised patients and premature infants.[47, 55] In premature infants, Lichtheimia infections furthermore commonly affect the gastrointestinal tract,[56] often resembling necrotising enterocolitis.[57] Since most studies on mucormycosis do not examine the type of infection on a species-specific level, it is hard to assess the incidence of

different types of infections for Lichtheimia. Only two studies include more detailed information about infections with Lichtheimia species. The study of Alvarez et al. included seven cases of Lichtheimia infections with pulmonary infection and infections of the sinuses as the most important presentations (6 of 7 cases).[22] Only one additional study focused on species-specific analysis of healthcare-associated mucormycosis. Cutaneous and pulmonary infections Selleck Fulvestrant were the most common types of infection representing 70% and 20% respectively.[83] However, due to the limitations of the currently available studies, e.g. low numbers of cases Anacetrapib or restriction to a special patient group, no clear conclusions can be drawn about the incidence of the different types of infections and underlying conditions for the development of Lichtheimia infections. In addition to causing infections, Lichtheimia species have been implicated in the form of occupational hypersensitivity pneumonitis termed Farmer’s lung disease (FLD). Farmer’s lung disease is caused by recurrent exposure to certain microorganisms, especially

in farming personnel. The acute form is characterised by influenza-like symptoms like sweating, chills, fever, nausea and headache. The (sub)chronic form is associated with coughing and dyspnoea for up to several weeks.[58] As mentioned above, Lichtheimia species represent a major contaminant of farming material like hay and straw. The occurrence of FLD has been associated with increased numbers of L. corymbifera in the farm environment and L. corymbifera-specific antibodies in affected patients.[59] Furthermore, in vitro experiments with lung epithelial cells revealed high expression of pro-inflammatory and allergic mediators (IL-8, IL-13) after exposure to extracts of L. corymbifera.[60] These results support the role of Lichtheimia in the development of hypersensitivity pneumonia.

In such cases, IL-2-mediated bystander activation of these pre-ac

In such cases, IL-2-mediated bystander activation of these pre-activated CD25+ CD4+ T cells by Ag-stimulated Ag-specific CD4+ memory T cells, as suggested by Di Genova et al. 12, could occur and boost suboptimal responses ABT-888 solubility dmso of the former, thus favoring chronic inflammation and immunopathology 17. Although “classic” IFN/IL-15-mediated bystander activation provides an explanation as to how resting heterologous CD8+ T cells are recruited to an ongoing immune response, the IL-2-dependent type of bystander activation focuses on recently activated CD4+ T cells. As CD4+ T cells can differentiate into many different

functional subsets and exert diverse functions 13, such CD4+ T-cell bystander activation might affect immune homeostasis in a very different way as compared with bystander activation of CD8+ T cells. Thus, it will be of interest to Peptide 17 molecular weight further investigate the fate of CD4+ T cells stimulated by IL-2-mediated bystander activation, as IL-2 is known to exert somewhat opposing functions in the immune system, being able to either promote cell survival or favor apoptosis depending on the circumstances 13. Likewise, previous work on bystander proliferation of CD4+ T cells

has also described opposing outcomes such as prolonged survival or rapid cell death 18, 19. Future studies will have to address these outstanding issues. This work was supported by a grant from the Swiss National Science Foundation (♯320000-118471). Conflict of interest: The author declares no

financial or commercial conflict of interest. See accompanying article: http://dx.doi.org/10.1002/eji.200940017 “
“Currently, placentitis, an important cause of late pregnancy loss in mares, is diagnosed by clinical signs and ultrasonography. Acute phase proteins (APP) are mainly produced and secreted by the liver in response to acute inflammatory stimuli. We hypothesized that APP are increased in mares with placentitis. Concentrations of serum amyloid A (SAA), haptoglobin (Hp), Fossariinae fibrinogen (Fb), and white blood cell counts (WBC) were determined in plasma of mares with experimentally induced placentitis and gestationally age-matched control mares. Placentitis was induced via intracervical inoculation of Streptococcus equi subspecies zooepidemicus, a common isolate from clinical cases of bacterial placentitis. Concentrations of SAA and Hp were also determined in the 10 days pre-partum in normal mares. Mares with placentitis aborted within 5–25 days after inoculation. Concentrations of SAA and Hp rapidly increased subsequent to experimental induction of placentitis and remained increased until abortion. Neither Fb nor WBC appeared to be useful markers for placentitis. Parturition did not trigger increase in either SAA or Hp in normal foaling mares.

Amphotericin B-Desoxycholat weist deutliche Nebenwirkungen bei i

Amphotericin B-Desoxycholat weist deutliche Nebenwirkungen bei i.v. Therapie auf. Die nordamerikanische Infectious Disease Society (IDSA) Guideline von 2008 empfiehlt Amphotericin B-Desoxycholat aufgrund substantieller Toxizitäten nur noch für Regionen mit eingeschränkten Ressourcen, die in nicht entwickelten

Ländern see more vorliegen können. Liposomales Amphotericin B in der Standarddosierung (3 mg/kg) weist ähnliche Ansprechraten wie Voriconazol in der Erstlinientherapie der invasiven Aspergillose auf. Allerdings fehlt ein direkter Vergleich mit Voriconazol aus randomisierten Studien. In der Zweitlinientherapie nach Versagen oder Intoleranz der Primärtherapie wurden in den letzten Jahren Caspofungin, Micafungin und Posaconazol untersucht. Kombinationstherapien werden bei refraktären Fällen einer invasiven Aspergillose im klinischen Alltag eingesetzt. Ergebnisse aus vergleichenden prospektiven kontrollierten Studien einer Kombinationstherapie gegenüber einer Monotherapie werden erst nach 2010 zu erwarten sein. Invasive

fungus infections caused by aspergillus spp. selleck products occur most frequently in immunocompromised patients. A high infection-associated death rate of up to and over 50% is attributed even today to these fungi. The disease in humans is caused mainly by Aspergillus fumigatus, Aspergillus flavus and Aspergillus niger. Other species, for example, Aspergillus terreus or Aspergillus nidulans are quantitatively less prevalent. Evidence based treatment of invasive aspergillosis has become safer and more effective within the last ten years through the introduction of the new azoles and the echinocandines. Voriconazole has become the medication of choice for initial therapy. The efficacy of voriconazole is well documented, to include the treatment of disseminated infections of the central nervous system. Amphotericin B-desoxycholate is associated with definite side-effects in intravenous therapy. On the grounds of its substantial toxicity, the North American Infectious Disease Society’s (IDSA) Guidelines of 2008 recommend amphotericin B-desoxycholate for regions with restricted resources only,

which could be the case in underdeveloped countries. Liposomal amphotericin B in the daily standard dose of 3 mg/kg offers a rate of response similar to the one with voriconazole in the first-line treatment of invasive aspergillosis. However, a direct Casein kinase 1 comparison with voriconazole on the basis of randomized studies is not available. As a secondary therapeutic treatment, in case of failure or intolerance of the primary treatment, caspofungin, micafungin and posaconazole have recently been under study. Both the echinocandines and posaconazole have proven effective in daily clinical practise. In refractory cases of invasive aspergillosis a combination therapy has been employed clinically. The results of prospective comparative controlled studies on combination therapy versus monotherapy will not be available until after 2010.

Likewise, Tconv derived from both

Likewise, Tconv derived from both beta-catenin inhibitor study cohorts had similar in vitro proliferative responses (data not shown) which is in line with previous findings

20. Moreover, altered IL-7Rα expression levels in MS were observable in both naïve and memory Tconv. Therefore, it is unlikely, that increased frequencies of recently activated cells with downregulated IL7Rα surface expression might account for the differences in IL-7Rα-MFIs between MS patients and healthy donors reported here. Collectively, our observations strongly suggest that signaling through IL-7/IL-7Rα is an important participant in Treg homeostasis and function despite their CD127low phenotype. In consistence, besides IL-2, IL-7 and other members of the common γ-chain receptor such as IL-4 and IL-15 were found to play a role in maintaining optimal suppressive potency of both human and murine Treg 9,

10. Of note, IL-7Rα together with TSLPR forms the receptor for find more TSLP. TSLP, released from epithelial cells of Hassall’s corpuscles in the thymic medulla activates both human thymic MDCs and plasmacytoid dendritic cells (PDC), which promote differentiation of CD4+CD8−CD25− thymocytes into Treg 13, 28. Moreover, signals from the IL-7 receptor are required for Treg development as shown in IL-7Rα knockout mice 14. Here, we found that TSLPR levels on peripheral MDC correlated well with IL-7Rα expression on Tconv and were significantly reduced on circulating MDC obtained from patients with MS. These observations indirectly suggest that a concomitant alteration of IL-7Rα/TSLPR expression in the thymic environment might negatively

interfere with Treg neogenesis. In consistence with this hypothesis, our finding of patient-derived Treg containing strikingly less cells expressing TCRs with dual specificity compared to Treg from healthy individuals is compatible with a contracted release of Treg from the thymus in patients with MS. Due to lack of allelic exclusion Chloroambucil in the TCR α locus two αβ-TCRs may be generated in a maturing thymocyte during the process of TCR gene rearrangement. Whereas TCRs with one common Vβ-chain but two distinct Vα-chains are detectable in at most one-third of Tconv, TCRs with dual specificity were found to be enriched in natural Treg 21. In our study, the percentages of Tconv expressing TCRs with both a Vα2+- and a Vα12+-chain were in the expected range of 27%, yet only 57% of patient-derived Treg versus 88% of donor Treg tested positive for a secondary TCR. The prevalences of Treg carrying TCRs of dual specificity also correlated with IL-7Rα- and TSLPR-MFIs on peripheral immune cells indicating that both IL-7/IL-7R and TSLP/TSLPR signaling might impact this intrinsic signature of thymus-derived Treg. The relevance of our observations is highlighted by recent findings in a murine model of experimental allergic encephalomyelitis (EAE).