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Poult enteritis syndrome (PES) is an infectious disease of turkey poults characterized by diarrhea, dullness, and depression. Five experiments were conducted to reproduce the disease in turkey poults using intestinal contents of PES-affected birds. In all experiments, poults at 14 d of age were divided into 4 groups and were orally given 2 mL of unfiltered supernatant, filtered supernatant, sediment dissolved in PBS, or PBS alone. Inocula in experiments 1, 3, and 5 consisted of intestinal contents from PES-affected birds of less than 2 wk of age, whereas those in experiments 2 and 4 consisted of intestinal contents from PES-affected birds of 4 to 6 wk of age. Poults in all groups were observed daily for clinical signs. The BW and microbiological criteria in experiments 1, 3, and 5 were evaluated at 5, 10, and 15 d postinoculation, whereas in experiments 2 and 4, these observations were made at 10 and 20 d postinoculation. Rotavirus, astrovirus, and Salmonella were present in all 5 inocula. Diarrhea and depression were the major signs in poults given PES material. Significant retardation of growth was observed in poults given any of the 3 PES materials, but this effect was more pronounced in poults given the sediment inoculum. Rotavirus, astrovirus, and Salmonella were detected in poults given PES material. In some cases, enterovirus was also detected. No major difference was noticed in experimental reproduction of PES when intestinal contents from different age birds were used as the inoculum.

Long-term survival after lung transplantation is limited by acute and chronic graft rejection. Induction of immune tolerance by first establishing mixed hematopoietic chimerism (MC) is a promising strategy to improve outcomes. In a preclinical canine model, stable MC was established in recipients after reduced-intensity conditioning and hematopoietic cell transplantation from a DLA-identical donor. Delayed lung transplantation was performed from the stem cell donor without pharmacological immunosuppression. Lung graft survival without loss of function was prolonged in chimeric (n = 5) vs. nonchimeric (n = 7) recipients (por = 0.05, Fisher's test). There were histological changes consistent with low-grade rejection in 3/5 of the lung grafts in chimeric recipients ator =1 year. Chimeric recipients after lung transplantation had a normal immune response to a T-dependent antigen. Compared to normal dogs, there were significant increases of CD4+INFgamma+, CD4+IL-4+ and CD8+ INFgamma+ T-cell subsets in the blood (p0.0001 for each of the three T-cell subsets). Markers for regulatory T-cell subsets including foxP3, IL10 and TGFbeta were also increased in CD3+ T cells from the blood and peripheral tissues of chimeric recipients after lung transplantation. Establishing MC is immunomodulatory and observed changes were consistent with activation of both the effector and regulatory immune response.

Earlier experiments [Eur. Phys. J. D 43, 241 (2007)] investigating the production of aluminium cluster dianions have been extended to larger cluster sizes for the purpose of producing higher charge states. Polyanions are produced using the “electron-bath technique" which involves the exposure of monoanionic clusters to a bath of low-energy secondary electrons. In this contribution the production of Aln 3- is investigated as a function of cluster size. Relative trianion yields (number of trianions produced relative to the number of precursor anions) were observed to increase from a few percent up to 55% within ~30 cluster sizes. The observed appearance size (n = 103) is in reasonable agreement with the predictions of classical models.

Imatinib is a receptor tyrosine kinase inhibitor that blocks the activity of c-Abl, c-Kit, and PDGF receptors. We tested the protective effects of imatinib in thymic stromal lymphopoietin transgenic mice, a model of cryoglobulinemia and associated membranoproliferative glomerulonephritis (MPGN), in which some glomerular manifestations likely result from PDGF receptor activation. Surprising, administration of imatinib beginning at weaning suppressed production of cryoglobulin, attenuating both the renal injury and systemic features of cryoglobulinemia. Flow cytometry suggested that inhibition of B cell development in the bone marrow likely caused the reduction in cryoglobulin production. In addition, administration of imatinib to thymic stromal lymphopoietin transgenic mice with established MPGN also diminished cryoglobulin production and reversed the renal and systemic lesions. These data suggest that treatment with imatinib may be a novel therapeutic approach for cryoglobulinemia and MPGN in humans.

Tolerance to self antigens is established in two ways: first in the thymus through the deletion of thymocytes expressing self-reactive T cell receptors; and second, in the periphery through multiple mechanisms involving deletion, anergy, and suppression. Dominant tolerance to self antigens in the periphery is primarily the function of the CD4(+)CD25(+)FOXP3(+) subset of T cells, which have the capability of suppressing autoreactive T cells that have escaped deletion during thymic selection. The essential role of the transcription factor FOXP3 in the development and function of these cells has been well documented. However, the underlying mechanisms by which FOXP3 controls this process are less well understood. This review will focus on the role of FOXP3 in regulating CD4 T cell function in both humans and mice, with an emphasis on recent work in human systems.

The epithelial-derived cytokine thymic stromal lymphopoietin (TSLP) is sufficient to induce asthma or atopic dermatitis-like phenotypes when selectively overexpressed in transgenic mice, or when driven by topical application of vitamin D3 or low-calcemic analogues. Although T and B cells have been reported to be dispensable for the TSLP-induced inflammation in these models, little is known about the downstream pathways or additional cell types involved in the inflammatory response driven by TSLP. To characterize the downstream effects of TSLP in vivo, we examined the effects of exogenous administration of TSLP protein to wild-type and genetically deficient mice. TSLP induced a systemic Th2 inflammatory response characterized by increased circulating IgE and IgG1 as well as increased draining lymph node size and cellularity, Th2 cytokine production in draining lymph node cultures, inflammatory cell infiltrates, epithelial hyperplasia, subcuticular fibrosis, and up-regulated Th2 cytokine and chemokine messages in the skin. Responses to TSLP in various genetically deficient mice demonstrated T cells and eosinophils were required, whereas mast cells and TNF-α were dispensable. TSLP-induced responses were significantly, but not completely reduced in IL-4- and IL-13-deficient mice. These results shed light on the pathways and cell types involved in TSLP-induced inflammation.

Thymic stromal lymphopoietin (TSLP) is a cytokine expressed by epithelial cells, including keratinocytes, and is important in allergic inflammation. Allergic skin inflammation elicited by epicutaneous immunization of mice with ovalbumin (OVA), a potential model of atopic dermatitis, was severely impaired in TSLPR −/− mice, as evidenced by decreased infiltration of eosinophils and decreased local expression of T helper 2 (Th2) cytokines. However, secretion of Th2 cytokines by splenocytes from epicutaneous sensitized TSLPR −/− mice in response to OVA was normal. Skin dendritic cells from TSLPR −/− mice were normal in their ability to migrate to draining lymph nodes, express activation markers, and induce proliferation and Th2 cytokine production by naïve T cells. CD4 + T cells from TSLPR −/− mice expressed the skin homing receptor E-selectin ligand normally, and homed to the skin normally, but failed to transfer allergic skin inflammation to WT recipients. TSLP enhanced Th2 cytokine secretion in vitro by targeting TSLPR on antigen specific T cells. Intradermal injection of anti-TSLP blocked the development of allergic skin inflammation after cutaneous antigen challenge of OVA immunized WT mice. These findings suggest that TSLP is essential for antigen driven Th2 cytokine secretion by skin infiltrating effector T cells and could be a therapeutic target in allergic skin inflammation.

Legislation over the past two decades has shaped the dominant view of adult literacy as addressing gaps in well-defined, measurable skills. As rural communities face unprecedented challenges, this one-size-fits-all view of adult literacy does not consider the unique local context of rural communities or involve those communities in defining their own needs and goals.

Thymic stromal lymphopoietin (TSLP) is an interleukin-7 (IL-7)-like cytokine involved in T helper 2 type immune responses. The primary target of TSLP is myeloid dendritic cells (DCs), however, little is known about the mechanism by which TSLP elicits respiratory IgA immune responses upon mucosal immunization. Here, we found that the levels of TSLP and TSLPR were upregulated in the mucosal DCs of mice nasally immunized with pneumococcal surface protein A (PspA) plus cholera toxin (CT) compared with those immunized with PspA alone. PspA-specific IgA responses, but not IgG Ab responses were significantly reduced in both serum and mucosal secretions of TSLPR knockout mice compared with wild-type mice after nasal immunization with PspA plus CT. Furthermore, CD11c+ mucosal DCs isolated from TSLPR knockout mice nasally immunized with PspA plus CT were less activated and exhibited markedly reduced expression of IgA-enhancing cytokines (e.g., APRIL, BAFF, and IL-6) compared with those from equivalently immunized wild-type mice. Finally, exogenous TSLP promoted production of IgAs in an in vitro DC-B cell co-culture system as exhibited by enhanced IL-6 production. These results suggest that TSLP-TSLPR signaling is pivotal in the induction of nasal respiratory immunity against pathogenic pneumococcal infection.

Although interest in narrative research is increasing, little attention has been paid to how individual stories become a group narrative. An online environment provides a rich opportunity to capture asynchronous group storytelling as it occurs in a formal class environment. This study focused on how a group story is created. Data included individual stories of four graduate student participants and the threads from their three-week, online discussion. Data analysis was collaborative among three researchers. The four participants used the online discussion to continue developing their own individual stories and to develop a group story. The women used temporality, shared themes, and epiphany to construct a story together. They extended a sense of agency to each other and to the group, using this aspect of their dialogue to reframe and recast individual stories and the group story. Implications for teaching and learning environments are discussed.

This work provides information pertaining to the performance of Silicon-On-Insulator (SOI) microdosimeters in heavy ion radiation fields. SOI microdosimeters have been previously tested in light ion radiation fields for both space and therapeutic applications, however their response has not been established in high energy, heavy ion radiation fields which are experienced in space. Irradiations were completed at the NASA Space Radiation Laboratory at BNL using 0.6 GeV/u Fe and 1.0 GeV/u Ti ions. Energy deposition and lineal energy spectra were obtained with this device at various depths within a Lucite phantom along the central axis of the beam. The response of which was compared with existing proportional counter data to assess the applicability of SOI microdosimeters to future deployments in space missions.

This paper discusses the effective limiting heavy-ion induced single-event upset cross section of radiation-hardened 150 nm SOI SRAM and the resistance of the active-delay element (ADE) used in the memory cell. The effective limiting upset cross-section of ADE/SRAM is found to be proportional to the product of the limiting upset cross-section of the 6T SRAM of the same CMOS technology and a dimensionless function of the normalized ADE resistance. In addition, a cross-section higher than this effective limiting cross-section at high effective LET (>250 MeV-cm2/mg) is observed. This additional contribution to the cross-section is attributed to the upset caused by the high effective LET heavy ion hitting the on-transistor in the memory cell.

Immunological tolerance to self antigens is a tightly regulated process. Recent work has demonstrated that the forkhead family member Foxp3 is a critical element in the differentiation and function of mouse CD4(+)CD25(+) regulatory T cells (Treg). Recent work has suggested an important role for IL-2 in the development and maintenance of Treg. To directly assess the effect of IL-2 signaling on Treg development and function, we analyzed mice that were genetically deficient in components of the IL-2 receptor (IL-2R). Mice lacking CD25 (IL-2Ralpha) displayed a slight decrease in Treg within the thymus, while peripheral numbers are unchanged. In contrast, we found that mice deficient in CD122 (IL-2Rbeta) had a profound reduction in both thymic and peripheral Treg, coinciding with more rapid development of a fatal lymphoproliferative disease. Expression of a Foxp3 transgene restored Treg and protected against the onset of autoimmunity. Thus, a signal mediated by IL-2Rbeta is essential for the development and homeostasis of Foxp3(+) Treg in vivo.

It is demonstrated how FT-ICR MS can be used to monitor both the coherent magnetron motion and the cyclotron motion of ions stored in a Penning trap. By use of the ICR signal intensity at the magnetron frequency, ν−, and the reduced cyclotron frequency, ν+, the manipulation of the ion motion by dipolar, quadrupolar, and octupolar excitation has been followed. In particular, the conversion between the magnetron and the cyclotron motion by quadrupolar and octupolar excitation at the corresponding resonance frequencies νc = ν+ + ν− and 2νc, respectively, has been observed by detection of the magnetron and the cyclotron signal. While the ion motion under the influence of a quadrupolar excitation has already been studied extensively, the octupolar excitation has been introduced only recently. As compared to other techniques, such as the time-of-flight ion-cyclotron-resonance detection method, FT-ICR MS allows to simultaneously investigate the influence of an excitation on the cyclotron und the magnetron motional modes.

Dendritic cells (DCs) are professional antigen-presenting cells that have the ability to sense infection and tissue stress, sample and present antigen to T lymphocytes, and induce different forms of immunity and tolerance. The functional versatility of DCs depends on their remarkable ability to translate collectively the information from both the invading microbes and their resident tissue microenvironments and then make an appropriate immune response. Recent progress in understanding TLR biology has illuminated the mechanisms by which DCs link innate and adaptive antimicrobial immune responses. However, how tissue microenvironments shape the function of DCs has remained elusive. Recent studies of TSLP (thymic stromal lymphopoietin), an epithelial cell–derived cytokine that strongly activates DCs, provide evidence at a molecular level that epithelial cells/tissue microenvironments directly communicate with DCs. We review recent progress on how TSLP expressed within thymus and peripheral lymphoid and nonlymphoid tissues regulates DC-mediated central tolerance, peripheral T cell homeostasis, and inflammatory Th2 responses.

The cytokine thymic stromal lymphopoietin (TSLP) drives immature B cell development in vitro and may regulate T helper type 2 responses. Here we analyzed the involvement of TSLP in B cell development in vivo with a doxycycline-inducible, keratin 5-driven transgene encoding TSLP (K5-TSLP). K5-TSLP-transgenic mice given doxycycline showed an influx of immature B cells into the periphery, with population expansion of follicular mature B cells, near-complete loss of marginal zone and marginal zone precursor B cells, and 'preferential' population expansion of peritoneal B-1b B cells. These changes promoted cryoglobulin production and immune complex-mediated renal disease. Identical events occurred in mice without T cells, in alternative TSLP-transgenic models and in K5-TSLP-transgenic mice with undetectable systemic TSLP. These observations suggest that signals mediating localized TSLP expression may modulate systemic B cell development and promote humoral autoimmunity.

Wiskott-Aldrich syndrome protein (WASp) is essential for optimal T cell activation. Patients with WAS exhibit both immunodeficiency and a marked susceptibility to systemic autoimmunity. We investigated whether alterations in Treg function might explain these paradoxical observations. While WASp-deficient (WASp(-/-)) mice exhibited normal thymic Treg generation, the competitive fitness of peripheral Tregs was severely compromised. The total percentage of forkhead box P3-positive (Foxp3(+)) Tregs among CD4(+) T cells was reduced, and WASp(-/-) Tregs were rapidly outcompeted by WASp(+) Tregs in vivo. These findings correlated with reduced expression of markers associated with self-antigen-driven peripheral Treg activation and homing to inflamed tissue. Consistent with these findings, WASp(-/-) Tregs showed a reduced ability to control aberrant T cell activation and autoimmune pathology in Foxp3(-/-)Scurfy (sf) mice. Finally, WASp(+) Tregs exhibited a marked selective advantage in vivo in a WAS patient with a spontaneous revertant mutation, indicating that altered Treg fitness likely explains the autoimmune features in human WAS.

The cytokine thymic stromal lymphopoietin (TSLP) has been implicated in the development and progression of allergic inflammation in both humans and mice. Although the underlying mechanism is not known, TSLP-stimulated dendritic cells have been shown to prime human CD4+ T cells into Th2 cytokine-producing cells. However, its direct effect on CD4+ T cells has not been extensively investigated. In this study, we show that TSLP can drive Th2 differentiation in the absence of exogenous IL-4 and APCs. IL-4 blockade inhibited TSLP-mediated Th2 differentiation, demonstrating that IL-4 is involved in this process. Further analysis has shown that TSLP-induced Th2 differentiation is dependent on Stat6 and independent of IL-2 and that TSLP treatment leads to immediate, direct Il-4 gene transcription. Taken together, these data demonstrate that TSLP is directly involved in Th2-mediated responses via the induction of IL-4 production.

Compelling evidence suggests that the epithelial cell–derived cytokine thymic stromal lymphopoietin (TSLP) may initiate asthma or atopic dermatitis through a dendritic cell–mediated T helper (Th)2 response. Here, we describe how TSLP might initiate and aggravate allergic inflammation in the absence of T lymphocytes and immunoglobulin E antibodies via the innate immune system. We show that TSLP, synergistically with interleukin 1 and tumor necrosis factor, stimulates the production of high levels of Th2 cytokines by human mast cells (MCs). We next report that TSLP is released by primary epithelial cells in response to certain microbial products, physical injury, or inflammatory cytokines. Direct epithelial cell–mediated, TSLP-dependent activation of MCs may play a central role in “intrinsic” forms of atopic diseases and explain the aggravating role of infection and scratching in these diseases.

The epithelial-derived cytokine thymic stromal lymphopoietin (TSLP) is important for the initiation of allergic airway inflammation through a dendritic cell-mediated T helper 2 response. To identify the factors that control TSLP expression, we examined the ability of inflammatory mediators to regulate TSLP production in human airway epithelial cells. We found that both IL-1β and TNF-α were capable of inducing rapid TSLP production in primary human bronchial airway epithelial cells. We further characterized the human TSLP gene promoter, using two human epithelial cell lines, 16HBEo − and A549, and showed that IL-1β- and TNF-α-mediated human TSLP promoter activation in these cells was mediated by an upstream NFκB site. Mutation of this NFκB site abolished activation, as did overexpression of a dominant-negative version of IκB kinase (IKK)β (a kinase acting on IκB, the inhibitor of NFκB). Interestingly, human TSLP mRNA levels were also increased after exposure to Toll-like receptor (TLR) 2, TLR8, and TLR9 ligands, further supporting an important role for NFκB in TSLP gene regulation. Similarly, analysis of the mouse TSLP gene promoter revealed the presence of a similarly situated NFκB site that was also critical for IL-1β-inducible expression of mouse TSLP. Taken together, these results demonstrate that the inflammatory mediators IL-1β and TNF-α regulate human TSLP gene expression in an NFκB-dependent manner.

Objective To investigate the efficacy of type II collagen–reactive Foxp3-expressing T cell transfer in suppressing collagen-induced arthritis (CIA) in relation to disease progression. Methods CD3-activated CD4 T cells were retrovirally transduced with the Foxp3 gene, and their in vitro suppressive activity on T cell proliferation was assessed for correlation with Foxp3 levels. To suppress CIA, Foxp3-transduced T cells generated with type II collagen– or ovalbumin (OVA)–pulsed dendritic cells (DCs), which were fractionated by Foxp3 levels, were adoptively transferred to mice at various time points. Results The in vitro suppressive activity of Foxp3-transduced cells correlated positively with Foxp3 levels. Type II collagen–reactive, but not OVA-reactive, Foxp3-transduced cells significantly suppressed CIA when they were transferred before immunization, and this suppression was accompanied by decreased anti–type II collagen antibody production. Larger cell numbers were required to suppress CIA when transfer occurred 20 days after immunization, indicating that hosts became resistant to suppression. Transfer of 1 × 105 Foxp3low cells had only a marginal effect on CIA suppression in immunized hosts, while transfer of Foxp3high cells at smaller doses significantly suppressed CIA. Transfer of 1 × 105 Foxp3high cells after establishment of arthritis attenuated disease progression but did not reverse joint swelling. Conclusion Resistance to Foxp3-transduced T cells proceeded as CIA progressed, suggesting that late-stage aggressive arthritis is more resistant to regulatory T cell transfer. An elevated expression level of Foxp3 in type II collagen–specific T cells improved their suppressive function in CIA. Thus, transfer of T cells expressing high levels of Foxp3 could be a strategy to overcome the induced resistance to regulatory T cell therapy.

Innate lymphoid cells (ILC) are a heterogeneous group of cellular subsets that produce large amounts of T cell–associated cytokines in response to innate stimulation in the absence of Ag. In this study, we define distinct patterns of surface marker and cytokine expression among the ILC subsets that may further delineate their migration and function. Most notably, we found that the subset previously defined as group 1 ILC (ILC1) contains CD4+ CD8−, CD4− CD8+, and CD4− CD8− populations. Although all ILC1 subsets shared characteristics with Th1 cells, CD4+ ILC1 also demonstrated significant phenotypic and functional heterogeneity. We also show that the frequencies of CD4+ ILC1 and NKp44+ group 3 ILC, but not CD4− ILC1 or group 2 ILC, are increased in the peripheral blood of individuals with systemic sclerosis (SSc), a disease characterized by fibrotic and vascular pathology, as well as immune dysregulation. Furthermore, we demonstrate that CD4+ and CD4− ILC1 are functionally divergent based on their IL-6Rα expression and that the frequency of IL-6Rα expression on ILC is altered in SSc. The distinct phenotypic and functional features of CD4+ and CD4− ILC1 suggest that they may have differing roles in the pathogenesis of immune-mediated diseases, such as SSc.

Much research has validated procedures to enhance reading fluency in children and adolescents, but more is needed to determine whether such procedures work with adults who have deficits in reading skills. A within-subjects design was used to evaluate and compare the effects of listening while reading (LWR) and repeated readings (RR) on reading fluency in adults reading at about fourth- or fifth-grade level. Results confirmed previous studies with children and adolescents that showed LWR and RR did increase reading fluency, but neither was more effective than the other. This study suggests that the opportunity to read with LWR caused the adult participants' increases in rereading fluency. Although adults and adolescents had similar responses to LWR and RR interventions, the adults' reading fluency appeared to increase more. This finding supports the need for more studies on whether strategies that have been empirically validated with children produce similar effects in adults.

This qualitative study explores how individuals made meaning of their life history experiences while in dialogue with others in an online learning group that was part of a graduate course on adult development. All online discussion forum postings exchanged by the group over the 3-week assignment period were downloaded and analyzed through phenomenological thematic analysis and discourse analysis. Our goal was to better understand both what happened in this online dialogue and how it took place. Four aspects of how the participants made meaning through dialogue emerged: noticing, reinterpreting, theorizing, and questioning assumptions, each with specific speech acts. These findings expand our understandings of how individuals transform meaning through narrative and dialogue. The identification of specific aspects of meaning making and their related speech acts make a contribution to the literature on online dialogue, the power of restorying, critical reflection in public meaning making, and transformative group learning.

Foxp3 has been shown to be both necessary and sufficient for the development and function of naturally arising CD4+CD25+ regulatory T cells in mice. Mutation of Foxp3 in Scurfy mice and FOXP3 in humans with IPEX results in fatal, early onset autoimmune disease and demonstrates the critical role of FOXP3 in maintaining immune homeostasis. The FOXP3 protein encodes several functional domains, including a C2H2 zinc finger, a leucine zipper, and a winged-helix/forkhead (FKH) domain. We have shown previously that FOXP3 functions as a transcriptional repressor and inhibits activation-induced IL-2 gene transcription. To characterize the role of each predicted functional domain on the in vivo activity of FOXP3, we have evaluated the location of point mutations identified in a large cohort of patients with the immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) and found them to cluster primarily within the FKH domain and the leucine zipper, but also present within the poorly defined N-terminal portion of the protein. The molecular functions of each of the IPEX-targeted domains were investigated. We show that FOXP3 is constitutively localized to the nucleus and this localization requires sequences at both the amino and C-terminal ends of its FKH domain. Moreover, FOXP3 was found to homodimerize through its leucine zipper. We also identify a novel functional domain within the N-terminal half of FOXP3, which is required for FOXP3-mediated repression of transcription from both a constitutively active and a NF-AT-inducible promoter. Furthermore, we demonstrate that IPEX mutations in these domains correlate with deficiencies in FOXP3 repressor function, corroborating their in vivo relevance.

MIDN (MIcroDosimetry iNstrument) is a payload on the MidSTAR-I spacecraft (Midshipman Space Technology Applications Research) under development at the United States Naval Academy. MIDN is a solid-state system being designed and constructed to measure microdosimetric spectra to determine radiation quality factors for space environments. Radiation is a critical threat to the health of astronauts and to the success of missions in low-Earth orbit and space exploration. The system will consist of three separate sensors, one external to the spacecraft, one internal and one embedded in polyethylene. Design goals are mass

Emerging evidence suggests critical roles for APCs in suppressing immune responses. Here, we show that zymosan, a stimulus for TLR2 and dectin-1, regulates cytokine secretion in DCs and macrophages to induce immunological tolerance. First, zymosan induces DCs to secrete abundant IL-10 but little IL-6 and IL-12(p70). Induction of IL-10 is dependent on TLR2- and dectin-1-mediated activation of ERK MAPK via a mechanism independent of the activation protein 1 (AP-1) transcription factor c-Fos. Such DCs stimulate antigen-specific CD4+ T cells poorly due to IL-10 and the lack of IL-6. Second, zymosan induces F4-80+ macrophages in the splenic red pulp to secrete TGF-beta. Consistent with these effects on APCs, injection of zymosan plus OVA into mice results in OVA-specific T cells that secrete little or no Th1 or Th2 cytokines, but secrete robust levels of IL-10, and are unresponsive to challenge with OVA plus adjuvant. Finally, coinjection of zymosan with OVA plus LPS suppresses the response to OVA via a mechanism dependent on IL-10, TGF-beta, and lack of IL-6. Together, our data demonstrate that zymosan stimulates IL-10+ IL-12(p70)- IL-6low regulatory DCs and TGF-beta+ macrophages to induce immunological tolerance. These data suggest several targets for pharmacological modulation of immune responses in various clinical settings.

CD4+CD25+ T regulatory (TR) cells are an important regulatory component of the adaptive immune system that limit autoreactive T cell responses in various models of autoimmunity. This knowledge was generated by previous studies from our lab and others using TR cell supplementation and depletion. Contrary to dogma, we report here that injection of anti-CD25 mAb results in the functional inactivation, not depletion, of TR cells, resulting in exacerbated autoimmune disease. Supporting this, mice receiving anti-CD25 mAb treatment display significantly lower numbers of CD4+CD25+ T cells but no change in the number of CD4+FoxP3+ TR cells. In addition, anti-CD25 mAb treatment fails to both reduce the number of Thy1.1+ congenic CD4+CD25+ TR cells or alter levels of CD25 mRNA expression in treatment recipients. Taken together, these findings have far-reaching implications for the interpretation of all previous studies forming conclusions about CD4+CD25+ TR cell depletion in vivo.

Adult literacy programs offer individuals, particularly women, opportunities to improve their educational levels and economic circumstances; however, persistence in these programs is an issue for many. Two hundred forty five participants in a statewide adult literacy program took the Adult Education Persistence Scale, a measure of self-efficacy, resilience, attitudes toward school, and attributions, a measure we developed in an effort to identify dispositional variables that predict persistence. Results indicated that dispositional variables modestly predicted persistence, identifying high and low attendees with 69% accuracy. We recommend screening for dispositional variables to identify those at risk for dropout and to provide relevant support.

The microdosimetric spectra derived by silicon microdosimeter in a proton radiation field traversing heterogeneous structures were simulated using the GEANT4 toolkit.

The forkhead-family transcription factor FoxP3 is important for the development and function of CD4+CD25+ regulatory T cells. While the overall phenotypic effects of FoxP3 expression are evident, the mechanism by which FoxP3 regulates T cell activation is not well understood. CD4+ T cells from mice that express a FoxP3 Tg are refractory to TCR-mediated stimulation, failing to proliferate or produce cytokines, but possess suppressive activity towards normal T cells. In this report we show that these T cells express elevated levels of mRNA for pro-apoptotic genes and undergo rapid apoptosis following stimulation. These T cells also display slower cell cycle transit following activation, suggesting that FoxP3 is capable of regulating the ability of T cells to respond to TCR-mediated activation. Lastly, we show that contrary to expected results, under Th1 or Th2 driving conditions, CD4+ T cells from FoxP3 Tg mice differentiate into effector cells. Concomitant with differentiation is a loss of FoxP3 mRNA and protein. These data demonstrate that FoxP3 levels regulate T cell function, and that FoxP3 itself is dynamically regulated during effector T cell differentiation.

Little is known about the molecules that control the development and function of CD4(+)CD25(+)Tregs. Recently, it was shown that the transcription factor FOXP3 is necessary and sufficient for the generation of CD4(+)CD25(+) Tregs in mice. We investigated the capacity of FOXP3 to drive the generation of suppressive CD4(+)CD25(+) Tregs in humans. Surprisingly, although ectopic expression of FOXR3 in human CD4(+) T cells resulted in induction of hyporesponsiveness and suppression of IL-2 production, it,did not lead to acquisition of significant suppressor activity in vitro. Similarly, ectopic expression of FOXP3 Delta 2, an isoform found in human CD4(+)CD25(+) Tregs that lacks exon 2, also failed to induce the development of suppressor T cells. Moreover, when FOXP3 and FOXP3 Delta 2 were simultaneously overexpressed, although the expression of several Treg-associated cell surface markers was significantly increased, only a modest suppressive activity was induced. These data indicate that in humans, overexpression of FOXP3 alone or together with FOXP3 Delta 2 is not an effective method to generate potent suppressor T cells in vitro and suggest that factors in addition to FOXP3 are required during the process of activation and/or differentiation for the development of bona fide Tregs.

The cytokine thymic stromal lymphopoietin (TSLP) has been linked to human allergic inflammatory diseases. We show here that TSLP expression was increased in the lungs of mice with antigen-induced asthma, whereas TSLP receptor-deficient mice had considerably attenuated disease. Lung-specific expression of a Tslp transgene induced airway inflammation and hyperreactivity characterized by T helper type 2 cytokines and increased immunoglobulin E. The lungs of Tslp-transgenic mice showed massive infiltration of leukocytes, goblet cell hyperplasia and subepithelial fibrosis. TSLP was capable of activating bone marrow-derived dendritic cells to upregulate costimulatory molecules and produce the T helper type 2 cell-attracting chemokine CCL17. These findings suggest that TSLP is an important factor necessary and sufficient for the initiation of allergic airway inflammation.

The cytokine thymic stromal lymphopoietin (TSLP) has recently been implicated in the pathogenesis of atopic dermatitis (AD) and other allergic diseases in humans. To further characterize its role in this disease process, transgenic mice were generated that express a keratinocyte-specific, tetracycline-inducible TSLP transgene. Skin-specific overexpression of TSLP resulted in an AD-like phenotype, with the development of eczematous lesions containing inflammatory dermal cellular infiltrates, a dramatic increase in Th2 CD4+ T cells expressing cutaneous homing receptors, and elevated serum levels of IgE. These transgenic mice demonstrate that TSLP can initiate a cascade of allergic inflammation in the skin and provide a valuable animal model for future study of this common disease.

Autoimmune diseases such as multiple sclerosis (MS) may result from the failure of tolerance mechanisms to prevent expansion of pathogenic T cells. Our study is the first to establish that MS patients have abnormalities in FOXP3 message and protein expression levels in peripheral CD4+CD25+ T cells (Tregs) that are quantitatively related to a reduction in functional suppression induced during suboptimal T-cell receptor (TCR) ligation. Of importance, this observation links a defect in functional peripheral immunoregulation to an established genetic marker that has been unequivocally shown to be involved in maintaining immune tolerance and preventing autoimmune diseases. Diminished FOXP3 levels thus indicate impaired immunoregulation by Tregs that may contribute to MS. Future studies will evaluate the effects of therapies known to influence Treg cell function and FOXP3 expression, including TCR peptide vaccination and supplemental estrogen. © 2005 Wiley-Liss, Inc.

Human immunodeficiency virus (HIV) disease is associated with loss of CD4+ T cells, chronic immune activation, and progressive immune dysfunction. HIV-specific responses, particularly those of CD4+ T cells, become impaired early after infection, before the loss of responses directed against other antigens; the basis for this diminution has not been elucidated fully. The potential role of CD25+CD4+ regulatory T cells (T reg cells), previously shown to inhibit immune responses directed against numerous pathogens, as suppressors of HIV-specific T cell responses was investigated. In the majority of healthy HIV-infected individuals, CD25+CD4+ T cells significantly suppressed cellular proliferation and cytokine production by CD4+ and CD8+ T cells in response to HIV antigens/peptides in vitro; these effects were cell contact dependent and IL-10 and TGF-β independent. Individuals with strong HIV-specific CD25+ T reg cell function in vitro had significantly lower levels of plasma viremia and higher CD4+: CD8+ T cell ratios than did those individuals in whom this activity could not be detected. These in vitro data suggest that CD25+CD4+ T reg cells may contribute to the diminution of HIV-specific T cell immune responses in vivo in the early stages of HIV disease.

The first NIST-traceable measurements of environmental thermal neutrons have been completed. The average sea level flux of thermal neutrons is 4 cm/sup 2//hr. This flux changes less than two times over wide varieties of terrain, in all weather conditions and over the solar year. The neutron flux is normalized to 39N-76.5W. This flux scales with geomagnetic Lat/Long and with altitude in a manner similar to the flux of incident energetic cosmic rays. The shielded flux has been measured under 450 g/cm/sup 2/, with a residual flux of 0.1 times the sea-level value. Preliminary shielding studies inside buildings and under water shows significant variability in the thermal neutron mean attenuation coefficient.

The nonpathogenic avian influenza (AI) outbreak in Pennsylvania began in December 1996 when there was a trace back from a New York live bird market to a dealer's flock. A total of 18 commercial layer flocks, two commercial layer pullet flocks, and a commercial meat turkey flock were diagnosed with nonpathogenic AI (H7N2) viral infection with an economic loss estimated at between 3 and 4 million dollars. Clinical histories of flocks infected with the disease included respiratory disease, elevated morbidity and mortality throughout the house, egg production drops, depression, and lethargy. A unique gross lesion in the commercial layers was a severe, transmural oviduct edema with white to gray flocculent purulent material in the lumen. Layer flocks on two separate premises were quarantined but permitted to remain in the facilities until cessation of virus shed was determined through virus isolation. Several months later, clinical AI appeared again in these flocks. It is not known whether the recurrence of disease in these cases is due to persistence of the organism in the birds or the environment. In addition to serologic testing and virologic testing by chicken embryo inoculation, an antigen capture enzyme immunoassay was evaluated as a diagnostic tool for AI. Research projects related to disinfection, burial pits, and geographical system technology were developed because of questions raised concerning transmission, diagnosis, and control of nonpathogenic AI (H7N2).

Scurfin, the protein product of the FoxP3 gene, is a forkhead-family transcription factor that negatively regulates T cell function. Mice carrying a loss-of-function mutation in FoxP3 (scurfy mice) present with fatal autoimmune-like disease caused by hyperresponsive CD4+ T cells. Mice that overexpress scurfin (FoxP3 Tg mice) possess fewer mature T cells with reduced functional capabilities compared with normal littermate control mice. We analyzed the ability of CD4+ T cells and B cells from FoxP3 Tg mice to respond to a T-dependent Ag and found that immunized FoxP3 Tg mice displayed reduced total and Ag-specific serum Ig and disorganized splenic architecture. However, when cultured in vitro, FoxP3 Tg B cells responded normally, suggesting that the poor Ab response was a result of defective T cell help in vivo. When challenged, CD4+ T cells from FoxP3 Tg mice display reduced up-regulation of CD40 ligand and fewer IFN-γ-producing cells. Overall, these findings show that overexpression of scurfin reduces T cell responses in vivo such that CD4+ T cells cannot provide help to B cells during a T cell-dependent Ab response.

The Pennsylvania egg quality assurance program (PEQAP) has made major gains in the reduction of Salmonella enterica serotype enteritidis (S. enteritidis). However, S. enteritidis continues to be a major food safety concern for the commercial egg laying industry. Despite intensive control efforts through PEQAP, some commercial egg layer houses still remain positive for S. enteritidis. The primary objective of this study was to determine whether S. enteritidis isolates obtained from historically environmentally S. enteritidis-positive houses were resistant to commonly used disinfectants. Archived S. enteritidis isolates (environmental, rodent, or egg) were compared with recently obtained isolates from the environment, rodents, or eggs from the same S. enteritidis-positive house. In addition, the isolates were compared with archived isolates from those premises that appeared to have eliminated S. enteritidis from their layer facilities. The official methods of the use-dilution analysis of the Association of Official Analytical Chemists were used to evaluate each disinfectant product. Two phenolic, one quaternary ammonium, and one combination product containing quaternary ammonium and formaldehyde were evaluated, in addition to one sodium hypochlorite detergent. All products diluted according to the manufacturers' recommendations killed the S. enteritidis isolates in this test system. There was no difference in susceptibility or resistance to the disinfectants used between the isolates from those facilities that remained S. enteritidis-positive and those that appeared to have eliminated S. enteritidis from their facility.

Correction to: Mucosal Immunology (2017); advance online publication, 28 June 2017; doi: 10.1038/mi.2017.61 The advance online publication version of this article included a spelling error in the title. The corrected title appears above and in the issue version of the article. The publisher regrets the error.