bluuebunny/crossref_metadata_2025_split huggingface dataset:
Umbilical Cord Blood T Cells Express Multiple Natural Cytotoxicity Receptors after IL-15 Stimulation, but Only NKp30 Is Functional
Authors: Tang Qin , Grzywacz Bartosz , Wang Hongbo , Kataria Nandini , Cao Qing , Wagner John E. , Blazar Bruce R. , Miller Jeffrey S. , Verneris Michael R. 
Published: April 2014

Abstract
The natural cytotoxicity receptors (NCRs) NKp30, NKp44, and NKp46 are thought to be NK lineage restricted. Herein we show that IL-15 induces NCR expression on umbilical cord blood (UCB) T cells. NCRs were mainly on CD8+ and CD56+ UCB T cells. Only NKp30 was functional as demonstrated by degranulation, IFN-γ release, redirected killing, and apoptosis. Since NCRs require adaptor proteins for function, the expressions of these adaptors were determined. The adaptors used by NKp30 and NKp46, FcεR1γ and CD3ζ, were detected in UCB T cells. There was a near absence of DAP12, the adaptor for NKp44, consistent with a hypofunctional state. NKp46 was on significantly fewer UCB T cells, possibly accounting for its lack of function. Adult peripheral blood (PB) T cells showed minimal NCR acquisition after culture with IL-15. Since UCB contains a high frequency of naive T cells, purified naive T cells from adult PB were tested. Although NKp30 was expressed on a small fraction of naive PB T cells, it was nonfunctional. In contrast to UCB, PB T cells lacked FcεR1γ expression. These results demonstrate differences between UCB and PB T cells regarding NCR expression and function. Such findings challenge the concept that NCRs are NK cell specific.
Regulatory T Cells Prevent Transfer of Type 1 Diabetes in NOD Mice Only When Their Antigen Is Present In Vivo
Authors: Tonkin Daniel R. , He Jing , Barbour Gene , Haskins Kathryn 
Published: April 2014

Abstract
Regulatory T cells (Tregs) can potentially be used as tools to suppress pathogenic T cells in autoimmune diseases such as type 1 diabetes. For use in therapy it is critically important to determine whether suppression by Tregs requires a population specific for the target of autoimmunity, such as pancreatic β cells in type 1 diabetes. Current reports in the NOD mouse model of type 1 diabetes are in conflict as to whether suppression of disease by Tregs is Ag-dependent. We have addressed this question by evaluating the effects of islet-specific TGF-β-induced Tregs in recipient mice in which the Treg Ag is either present or absent. Our data show that Treg numbers in pancreas are reduced in the absence of Ag and that there are Ag-dependent differences in the effects of Tregs on pathogenic T cells in the pancreas. By examining protection from diabetes induced by T cell transfer, we have clearly demonstrated that Tregs suppress only in the presence of their Ag and not in mice in which the islets lack the Treg Ag. Our results also suggest that in sufficiently large populations of polyclonal Tregs, there will be adequate numbers of islet-specific Tregs to suppress diabetes.
Promoter Analysis Reveals Critical Roles for SMAD-3 and ATF-2 in Expression of IL-23 p19 in Macrophages
Authors: Al-Salleeh Fahd , Petro Thomas M. 
Published: April 2014

Abstract
IL-23 p19/p40, produced by macrophages and dendritic cells, is critical for development of Th17 in several autoimmune diseases. In this study, bone marrow-derived (BMM) and splenic macrophages (SPM) from SJL/J mice, susceptible to autoimmune demyelinating disease following Theiler’s virus (TMEV) infection, expressed IL-23 in response to TMEV. We identified potential binding sites for IFN response factor (IRF)-3 (nt −734 to −731), Sma- and Mad-related protein (SMAD)-3 (nt −584 to −581), activating transcription factor (ATF)-2 (nt −571 to −568), IRF-7 (nt −533 to-525), and NF-κB (nt −215 to −209) in the murine p19 promoter. The p19prom in the pGL3 promoter-reporter vector responded to TMEV or poly(I:C), a TLR3 agonist in the RAW264.7 macrophage cell line. Deletions upstream from the IRF-3 site and mutations at the IRF-3, SMAD-3, ATF-2, or NF-κB, but not the IRF-7, sites significantly reduced promoter activity. ATF-2 or SMAD-3, but not IRF-3, short-hairpin RNA reduced p19 promoter activity and protein expression in RAW264.7 cells responding to TMEV. Chromosomal DNA immunoprecipitation assays revealed that SMAD-3 and ATF-2 bind to the endogenous p19 promoter in RAW264.7 cells and SJL/J SPM following challenge with TMEV. TGF-β1, which activates SMAD-3, was induced in RAW264.7 cells, BMM, and SPM by TMEV. Neutralizing Ab to TGF-β1 eliminated TMEV-induced IL-23 production and SMAD-3 activation in RAW264.7 cells, BMM, and SPM. Activation of ATF-2 was JNK, but not p38 or ERK MAPK dependent. Inhibition of the JNK, but also the ERK MAPK pathways decreased expression of p19. These results suggest that ATF-2 and SMAD-3 are transcription factors, which are, in addition to NF-κB, essential for IL-23 p19 expression.
Donor Deficiency of Decay-Accelerating Factor Accelerates Murine T Cell-Mediated Cardiac Allograft Rejection
Authors: Pavlov Vasile , Raedler Hugo , Yuan Shuguang , Leisman Staci , Kwan Wing-hong , Lalli Peter N. , Medof M. Edward , Heeger Peter S. 
Published: April 2014

Abstract
Decay-accelerating factor (DAF) is a cell surface regulator that accelerates the dissociation of C3/C5 convertases and thereby prevents the amplification of complement activation on self cells. In the context of transplantation, DAF has been thought to primarily regulate antibody-mediated allograft injury, which is in part serum complement-dependent. Based on our previously delineated link between DAF and CD4 T cell responses, we evaluated the effects of donor Daf1 (the murine homolog of human DAF) deficiency on CD8 T cell-mediated cardiac allograft rejection. MHC-disparate Daf1−/− allografts were rejected with accelerated kinetics compared with wild-type grafts. The accelerated rejection predominantly tracked with DAF’s absence on bone marrow-derived cells in the graft and required allograft production of C3. Transplantation of Daf1−/− hearts into wild-type allogeneic hosts augmented the strength of the anti-donor (direct pathway) T cell response, in part through complement-dependent proliferative and pro-survival effects on alloreactive CD8 T cells. The accelerated allograft rejection of Daf1−/− hearts occurred in recipients lacking anti-donor Abs. The results reveal that donor DAF expression, by controlling local complement activation on interacting T cell APC partners, regulates the strength of the direct alloreactive CD8+ T cell response. The findings provide new insights into links between innate and adaptive immunity that could be exploited to limit T cell-mediated injury to an allograft following transplantation.
T Cells from Leishmania major-Susceptible BALB/c Mice Have a Defect in Efficiently Up-Regulating CXCR3 upon Activation
Authors: Barbi Joseph , Brombacher Frank , Satoskar Abhay R. 
Published: April 2014

Abstract
Genetic background influences the outcome of Leishmania major infection. C57BL/6 mice mount a Th1 response and resolve infection. In contrast, BALB/c mice mount a Th2 response and develop chronic lesions. This susceptible phenotype is seen even though BALB/c mice generate IFN-γ-producing T cells at proportions similar to C57BL/6 mice in their lymph nodes (LN) early after infection. We had previously shown that chemokine receptor CXCR3 mediates immunity against L. major by recruiting IFN-γ-producing T cells to the lesions of C57BL/6 mice. Therefore, we hypothesized that IFN-γ-secreting T cells in BALB/c mice are unable to confer protection because they may be defective in up-regulating CXCR3. To test this hypothesis, we analyzed kinetics of CXCR3-expressing T cells in the LN and lesions of BALB/c and C57BL/6 mice during L. major infection. Additionally, we compared the ability of T cells from BALB/c and C57BL/6 mice to up-regulate CXCR3 upon activation. We found that resolution of L. major infection in C57BL/6 mice was associated with an increase in the proportion of CXCR3+ T cells in regional LN and lesions, whereas disease progression in BALB/c mice was associated with a decrease in these populations. Anti-CD3/CD28-activated T cells from naive BALB/c but not C57BL/6 mice were defective in up-regulating CXCR3. Impaired induction of CXCR3 on BALB/c T cells was not due to lack of IFN-γ and was mediated partially by IL-10 but not IL-4 or IL-13. We propose that defective CXCR3 up-regulation on T cells in BALB/c mice may contribute to L. major susceptibility.
Induction of a VLA-2 (CD49b)-Expressing Effector T Cell Population by a Cell-Based Neuroblastoma Vaccine Expressing CD137L
Authors: Yan Xiaocai , Johnson Bryon D. , Orentas Rimas J. 
Published: April 2014

AbstractIn malignancies where no universally expressed dominant Ag exists, the use of tumor cell-based vaccines has been proposed. We have modified a mouse neuroblastoma cell line to express either CD80 (B7.1), CD137L (4-1BBL), or both receptors on the tumor cell surface. Vaccines expressing both induce a strong T cell response that is unique in that among responding CD8 T cells, a T effector memory cell (TEM) response arises in which a large number of the TEM express the α-chain of VLA-2, CD49b. We demonstrate using both in vitro and in vivo assays that the CD49b+ CD8 T cell population is a far more potent antitumor effector cell population than nonfractionated CD8 or CD49b− CD8 T cells and that CD49b on vaccine-induced CD8 T cells mediates invasion of a collagen matrix. In in vivo rechallenge studies, CD49b+ T cells no longer expanded, indicating that CD49b TEM expansion is restricted to the initial response to vaccine. To demonstrate a mechanistic link between the expression of costimulatory molecules on the vaccine and CD49b on responding T cells, we stimulated naive T cells in vitro with artificial APC expressing different combinations of anti-CD3, anti-CD28, and CD137L. Although some mRNA encoding CD49b was induced by combining anti-CD3 with anti-CD28 or CD137L, the highest level was induced when all three signals were present. This indicates that CD49b expression results from additive costimulation and that the level of CD49b message serves as an indicator of the effectiveness of T cell activation by a cell-based vaccine.
Intrinsic and Induced Regulation of the Age-Associated Onset of Spontaneous Experimental Autoimmune Encephalomyelitis
Authors: Zhang Hong , Podojil Joseph R. , Luo Xunrong , Miller Stephen D. 
Published: April 2014

Abstract
Multiple sclerosis is characterized by perivascular CNS infiltration of myelin-specific CD4+ T cells and activated mononuclear cells. TCR transgenic mice on the SJL background specific for proteolipid protein (PLP)139–151 develop a high incidence of spontaneous experimental autoimmune encephalomyelitis (sEAE). We examined the intrinsic mechanisms regulating onset and severity of sEAE. CD4+ T cells isolated from the cervical lymph nodes, but not spleens, of diseased 5B6 transgenic mice are hyperactivated when compared with age-matched healthy mice and produce both IFN-γ and IL-17, indicating that the cervical lymph node is the initial peripheral activation site. The age-associated development of sEAE correlates with a decline in both the functional capacity of natural regulatory T cells (nTregs) and in PLP139–151-induced IL-10 production and a concomitant increase in IL-17 production. Anti-CD25-induced inactivation of nTregs increased the incidence and severity of sEAE. Conversely, induction of peripheral tolerance via the i.v. injection of PLP139–151-pulsed, ethylcarbodiimide-fixed APCs (PLP139–151-SP) inhibited the development of clinical disease concomitant with increased production of IL-10 and conversion of Foxp3+ Tregs from CD4+CD25− progenitors. These data indicate that heterogeneous populations of Tregs regulate onset of sEAE, and that induction of peripheral tolerance can be exploited to prevent/treat spontaneous autoimmune disease.
Swift Entry of Myelin-Specific T Lymphocytes into the Central Nervous System in Spontaneous Autoimmune Encephalomyelitis
Authors: Furtado Gláucia C. , Marcondes Maria Cecilia G. , Latkowski Jo-Ann , Tsai Julia , Wensky Allen , Lafaille Juan J. 
Published: April 2014

Abstract
Strong evidence supports that CNS-specific CD4+ T cells are central to the pathogenesis of multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). Using a model of spontaneous EAE, we demonstrated that myelin basic protein (MBP)-specific CD4+ T cells up-regulate activation markers in the CNS-draining cervical lymph nodes at a time when there is no T cell activation anywhere else, including the CNS, and before the appearance of clinical signs. In spontaneous EAE, the number of MBP-specific T cell numbers does not build up gradually in the CNS; instead, a swift migration of IFN-γ-producing T cells into the CNS takes place ∼24 h before the onset of neurological signs of EAE. Surgical excision of the cervical lymph nodes in healthy pre-EAE transgenic mice delayed the onset of EAE and resulted in a less severe disease. In EAE induced by immunization with MBP/CFA, a similar activation of T cells in the draining lymph nodes of the injection site precedes the disease. Taken together, our results suggest that peripheral activation of T cells in draining lymph nodes is an early event in the development of EAE, which paves the way for the initial burst of IFN-γ-producing CD4+ T cell into the CNS.
Novel Role of IL-13 in Fibrosis Induced by Nonalcoholic Steatohepatitis and Its Amelioration by IL-13R-Directed Cytotoxin in a Rat Model
Authors: Shimamura Takeshi , Fujisawa Toshio , Husain Syed R. , Kioi Mitomu , Nakajima Atsushi , Puri Raj K. 
Published: April 2014

Abstract
Nonalcoholic steatohepatitis (NASH), the most common cause of chronic liver fibrosis, progresses to cirrhosis in up to 20% of patients. We report that hepatic stellate cells (HSC) in sinusoidal lesions of liver of patients with NASH express high levels of high-affinity IL-13R (IL-13Rα2), which is colocalized with smooth muscle actin, whereas fatty liver and normal liver specimens do not express IL-13Rα2. HSCs engineered to overexpress IL-13Rα2 respond to IL-13 and induce TGFB1 promoter activity and TGF-β1 production. We also developed NASH in rats by feeding a choline-deficient l-amino acid diet. These rats developed liver fibrosis as assessed by H&E staining, Masson’s trichrome and Sirius red staining, and hydroxyproline assays. Treatment of these rats with IL-13R-directed cytotoxin caused a substantial decline in fibrosis and liver enzymes without organ toxicity. These studies demonstrate that functional IL-13Rα2 are overexpressed in activated HSCs involved in NASH and that IL-13 cytotoxin ameliorates pathological features of NASH in rat liver, indicating a novel role of this cytotoxin in potential therapy.
A Novel Role for CD4+ T Cells in the Control of Cachexia
Authors: Wang Zhuangzhi , Zhao Chunfang , Moya Rosa , Davies Joanna D. 
Published: April 2014

Abstract
Cachexia is the dramatic weight loss and muscle atrophy seen in chronic disease states, including autoimmunity, cancer, and infection, and is often associated with lymphopenia. We have previously shown that CD4+ T cells that express the lowest density of CD44 (CD4+CD44v.low) are significantly reduced in diabetic NOD mice that are cachexic compared with diabetic mice that are not cachexic. Using this model, and a model of cancer cachexia, we test the hypothesis that CD4+CD44v.low cells play an active role in protecting the host from cachexia. CD4+CD44v.low cells, but not CD4+ cells depleted of CD44v.low cells, delay the onset of wasting when infused into either diabetic or prediabetic NOD recipients. However, no significant effect on the severity of diabetes was detected. In a model of cancer cachexia, they significantly reduce muscle atrophy, and inhibit muscle protein loss and DNA loss, even when given after the onset of cachexia. Protection from wasting and muscle atrophy by CD4+CD44v.low cells is associated with protection from lymphopenia. These data suggest, for the first time, a role for an immune cell subset in protection from cachexia, and further suggest that the mechanism of protection is independent of protection from autoimmunity.
Goblet Cell-Derived Resistin-Like Molecule β Augments CD4+ T Cell Production of IFN-γ and Infection-Induced Intestinal Inflammation
Authors: Nair Meera G. , Guild Katherine J. , Du Yurong , Zaph Colby , Yancopoulos George D. , Valenzuela David M. , Murphy Andrew , Stevens Sean , Karow Margaret , Artis David 
Published: April 2014

Abstract
The secreted goblet cell-derived protein resistin-like molecule β (RELMβ) has been implicated in divergent functions, including a direct effector function against parasitic helminths and a pathogenic function in promoting inflammation in models of colitis and ileitis. However, whether RELMβ influences CD4+ T cell responses in the intestine is unknown. Using a natural model of intestinal inflammation induced by chronic infection with gastrointestinal helminth Trichuris muris, we identify dual functions for RELMβ in augmenting CD4+ Th1 cell responses and promoting infection-induced intestinal inflammation. Following exposure to low-dose Trichuris, wild-type C57BL/6 mice exhibit persistent infection associated with robust IFN-γ production and intestinal inflammation. In contrast, infected RELMβ−/− mice exhibited a significantly reduced expression of parasite-specific CD4+ T cell-derived IFN-γ and TNF-α and failed to develop Trichuris-induced intestinal inflammation. In in vitro T cell differentiation assays, recombinant RELMβ activated macrophages to express MHC class II and secrete IL-12/23p40 and enhanced their ability to mediate Ag-specific IFN-γ expression in CD4+ T cells. Taken together, these data suggest that goblet cell-macrophage cross-talk, mediated in part by RELMβ, can promote adaptive CD4+ T cell responses and chronic inflammation following intestinal helminth infection.
IL-33 Induces Antigen-Specific IL-5+ T Cells and Promotes Allergic-Induced Airway Inflammation Independent of IL-4
Authors: Kurowska-Stolarska Mariola , Kewin Pete , Murphy Grace , Russo Remo C. , Stolarski Bartosz , Garcia Cristiana Couto , Komai-Koma Mousa , Pitman Nick , Li Yubin , McKenzie Andrew N. J. , Teixeira Mauro M. , Liew Foo Y. , Xu Damo 
Published: April 2014

Abstract
Type 2 cytokines (IL-4, IL-5, and IL-13) play a pivotal role in helminthic infection and allergic disorders. CD4+ T cells which produce type 2 cytokines can be generated via IL-4-dependent and -independent pathways. Although the IL-4-dependent pathway is well documented, factors that drive IL-4-independent Th2 cell differentiation remain obscure. We report here that the new cytokine IL-33, in the presence of Ag, polarizes murine and human naive CD4+ T cells into a population of T cells which produce mainly IL-5 but not IL-4. This polarization requires IL-1R-related molecule and MyD88 but not IL-4 or STAT6. The IL-33-induced T cell differentiation is also dependent on the phosphorylation of MAPKs and NF-κB but not the induction of GATA3 or T-bet. In vivo, ST2−/− mice developed attenuated airway inflammation and IL-5 production in a murine model of asthma. Conversely, IL-33 administration induced the IL-5-producing T cells and exacerbated allergen-induced airway inflammation in wild-type as well as IL-4−/− mice. Finally, adoptive transfer of IL-33-polarized IL-5+IL-4−T cells triggered airway inflammation in naive IL-4−/− mice. Thus, we demonstrate here that, in the presence of Ag, IL-33 induces IL-5-producing T cells and promotes airway inflammation independent of IL-4.
Activation of Invariant NKT Cells Ameliorates Experimental Ocular Autoimmunity by A Mechanism Involving Innate IFN-γ Production and Dampening of the Adaptive Th1 and Th17 Responses
Authors: Grajewski Rafael S. , Hansen Anna M. , Agarwal Rajeev K. , Kronenberg Mitchell , Sidobre Stephane , Su Shao Bo , Silver Phyllis B. , Tsuji Moriya , Franck Richard W. , Lawton Anne P. , Chan Chi-Chao , Caspi Rachel R. 
Published: April 2014

AbstractInvariant NKT cells (iNKT cells) have been reported to play a role not only in innate immunity but also to regulate several models of autoimmunity. Furthermore, iNKT cells are necessary for the generation of the prototypic eye-related immune regulatory phenomenon, anterior chamber associated immune deviation (ACAID). In this study, we explore the role of iNKT cells in regulation of autoimmunity to retina, using a model of experimental autoimmune uveitis (EAU) in mice immunized with a uveitogenic regimen of the retinal Ag, interphotoreceptor retinoid-binding protein. Natural strain-specific variation in iNKT number or induced genetic deficiencies in iNKT did not alter baseline susceptibility to EAU. However, iNKT function seemed to correlate with susceptibility and its pharmacological enhancement in vivo by treatment with iNKT TCR ligands at the time of uveitogenic immunization reproducibly ameliorated disease scores. Use of different iNKT TCR ligands revealed dependence on the elicited cytokine profile. Surprisingly, superior protection against EAU was achieved with α-C-GalCer, which induces a strong IFN-γ but only a weak IL-4 production by iNKT cells, in contrast to the ligands α-GalCer (both IFN-γ and IL-4) and OCH (primarily IL-4). The protective effect of α-C-GalCer was associated with a reduction of adaptive Ag-specific IFN-γ and IL-17 production and was negated by systemic neutralization of IFN-γ. These data suggest that pharmacological activation of iNKT cells protects from EAU at least in part by a mechanism involving innate production of IFN-γ and a consequent dampening of the Th1 as well as the Th17 effector responses.
NFATc1 Regulates PD-1 Expression upon T Cell Activation
Authors: Oestreich Kenneth J. , Yoon Hyesuk , Ahmed Rafi , Boss Jeremy M. 
Published: April 2014

Abstract
PD-1 is a transmembrane protein involved in the regulation of immunological tolerance. Multiple studies have reported an association between high levels of PD-1 expressed on T cell surfaces and exhaustion in lymphocyte populations when challenged by chronic viral infections, such as HIV. By using model systems consisting of murine EL4 cells, which constitutively express PD-1, and primary murine CD8 T cells that express PD-1 upon T cell stimulation, we have identified two tissue-specific hypersensitive sites at the 5′ CR of the PD-1 locus. Gene reporter assays in CD8 T cells have shown that one of these sites has robust transcriptional activity in response to cell stimulation. Cell treatment with the calcineurin inhibitor cyclosporine A or a NFAT-specific inhibitor led to a sharp reduction in PD-1 expression in the constitutive and inducible systems. Furthermore, analysis of this region by chromatin immunoprecipitation assay revealed NFATc1 binding associated with gene activation in EL4 and primary CD8 T cells. Mutation of the NFATc1 binding site in PD-1 reporter constructs resulted in a complete loss of promoter activity. Together, these results demonstrate that PD-1 gene regulation occurs in part via the recruitment of NFATc1 to a novel regulatory element at the pdcd1 locus and provides the molecular mechanism responsible for the induction of PD-1 in response to T cell stimulation.