bluuebunny/crossref_metadata_2025_split huggingface dataset:
T Cell Ig- and Mucin-Domain-Containing Molecule-3 (TIM-3) and TIM-1 Molecules Are Differentially Expressed on Human Th1 and Th2 Cells and in Cerebrospinal Fluid-Derived Mononuclear Cells in Multiple Sclerosis
Authors: Khademi Mohsen , Illés Zsolt , Gielen Alexander W. , Marta Monica , Takazawa Naruhiko , Baecher-Allan Claire , Brundin Lou , Hannerz Jan , Martin Claes , Harris Robert A. , Hafler David A. , Kuchroo Vijay K. , Olsson Tomas , Piehl Fredrik , Wallström Erik 
Published: April 2014

Abstract
T cell Ig- and mucin-domain-containing molecules (TIMs) comprise a recently described family of molecules expressed on T cells. TIM-3 has been shown to be expressed on murine Th1 cell clones and has been implicated in the pathogenesis of Th1-driven experimental autoimmune encephalomyelitis. In contrast, association of TIM-1 polymorphisms to Th2-related airway hyperreactivity has been suggested in mice. The TIM molecules have not been investigated in human Th1- or Th2-mediated diseases. Using real-time (TaqMan) RT-PCR, we show that human Th1 lines expressed higher TIM-3 mRNA levels, while Th2 lines demonstrated a higher expression of TIM-1. Analysis of cerebrospinal fluid mononuclear cells obtained from patients with multiple sclerosis revealed significantly higher mRNA expression of TIM-1 compared with controls. Moreover, higher TIM-1 expression was associated with clinical remissions and low expression of IFN-γ mRNA in cerebrospinal fluid mononuclear cells. In contrast, expression of TIM-3 correlated well with high expression of IFN-γ and TNF-α. These data imply the differential expression of human TIM molecules by Th1 and Th2 cells and may suggest their differential involvement in different phases of a human autoimmune disease.
In a Transgenic Model of Spontaneous Autoimmune Diabetes, Expression of a Protective Class II MHC Molecule Results in Thymic Deletion of Diabetogenic CD8+ T Cells
Authors: Morgan David J. , Nugent C. Thomas , Raveney Benjamin J. E. , Sherman Linda A. 
Published: April 2014

Abstract
H-2d mice expressing both the influenza virus hemagglutinin (HA) as a transgene-encoded protein on pancreatic islet β cells (InsHA), as well as the Clone 4 TCR specific for the dominant H-2Kd-restricted HA epitope, can be protected from the development of spontaneous autoimmune diabetes by expression of the H-2b haplotype. Protection occurs due to the deletion of KdHA-specific CD8+ T cells. This was unexpected as neither the presence of the InsHA transgene nor H-2b, individually, resulted in thymic deletion. Further analyses revealed that thymic deletion required both a hybrid MHC class II molecule, Eβb Eαd, and the Kd molecule presenting the HA epitope, which together synergize to effect deletion of CD4+CD8+ thymocytes. This surprising example of protection from autoimmunity that maps to a class II MHC molecule, yet effects an alteration in the CD8+ T cell repertoire, suggests that selective events in the thymus represent the integrated strength of signal delivered to each cell through recognition of a variety of different MHC-peptide ligands.
Liver Dendritic Cells Are Less Immunogenic Than Spleen Dendritic Cells because of Differences in Subtype Composition
Authors: Pillarisetty Venu G. , Shah Alaap B. , Miller George , Bleier Joshua I. , DeMatteo Ronald P. 
Published: April 2014

AbstractThe unique immunological properties of the liver may be due to the function of hepatic dendritic cells (DC). However, liver DC have not been well characterized because of the difficulty in isolating adequate numbers of cells for analysis. Using immunomagnetic bead and flow cytometric cell sorting, we compared freshly isolated murine liver and spleen CD11c+ DC. We found that liver DC are less mature, capture less Ag, and induce less T cell stimulation than spleen DC. Nevertheless, liver DC were able to generate high levels of IL-12 in response to CpG stimulation. We identified four distinct subtypes of liver DC based on the widely used DC subset markers CD8α and CD11b. Lymphoid (CD8α+CD11b−) and myeloid (CD8α−CD11b+) liver DC activated T cells to a similar degree as did their splenic DC counterparts but comprised only 20% of all liver DC. In contrast, the two more prevalent liver DC subsets were only weakly immunostimulatory. Plasmacytoid DC (B220+) accounted for 19% of liver DC, but only 5% of spleen DC. Our findings support the widely held notion that liver DC are generally weak activators of immunity, although they are capable of producing inflammatory cytokines, and certain subtypes potently activate T cells.
IL-10 Induces Regulatory T Cell Apoptosis by Up-Regulation of the Membrane Form of TNF-α
Authors: Marra Luciano E. , Zhang Zhu X. , Joe Betty , Campbell Jon , Levy Gary A. , Penninger Josef , Zhang Li 
Published: April 2014

Abstract
Numerous studies have demonstrated the role of regulatory T (Treg) cells in peripheral tolerance. Nevertheless, how the survival and death of Treg cells is controlled is largely unknown. In this study, we investigated the mechanisms involved in regulating the homeostasis of a subset of Ag-specific αβTCR+ CD4−CD8− double negative (DN) Treg cells. We demonstrate that DN Treg cells are naturally resistant to TCR cross-linking-induced apoptosis. Administration of exogenous IL-10 renders DN Treg cells susceptible to apoptosis, and abolishes their suppressive function. Furthermore, TCR cross-linking of DN Treg cells in the presence of IL-10 leads to the up-regulation of the membrane-bound but not the soluble form of TNF-α. Interaction of membrane bound TNF-α with TNFR2 sends death signals to DN Treg cells. Blocking their interaction can reverse the effects of IL-10 on DN Treg cells. These results provide insights into the mechanisms that regulate the function and homeostasis of DN Treg cells.
Allelic Variation at theVHaLocus in Natural Populations of Rabbit (Oryctolagus cuniculus, L.)
Authors: Esteves Pedro J. , Lanning Dennis , Ferrand Nuno , Knight Katherine L. , Zhai Shi-Kang , van der Loo Wessel 
Published: April 2014

AbstractThe large interallelic distances between the three rabbit Ig VHa lineages, a1, a2 and a3, suggest that the persistence time of the VHa polymorphism could amount to 50 million years, which is much longer than that of MHC polymorphisms. Rabbit originated in the Iberian Peninsula where two subspecies coexist, one of which is confined to Southwestern Iberia (Oryctolagus cuniculus algirus). We studied the VH loci in the original species range to obtain a better understanding of the evolutionary history of this unusual polymorphism. Serological surveys revealed that sera from the subspecies algirus, when tested with VHa locus-specific alloantisera, showed either cross-reactivity (“a-positive” variants) or no reaction at all (“a-blank”). Using RT-PCR, we determined 120 sequences of rearranged VH genes expressed in seven algirus rabbits that were typed as either a-positive or a-blank. The data show that the VH genes transcribed in a-positive rabbits are closely related to the VH1 alleles of domestic rabbits. In contrast, a-blank rabbits were found to preferentially use VH genes that, although clearly related to the known VHa genes, define a new major allotypic lineage, designated a4. The a4 sequences have hallmark rabbit VHa residues together with a number of unprecedented amino acid changes in framework region 2 and 3. The net protein distances between the VHa4 and the VHa1, a2, and a3 lineages were 20, 29, and 21% respectively. We conclude that at least four distantly related lineages of the rabbit VHa locus exist, one of which seems to be endemic in the Iberian range.
Genomic Ly49A Transgenes: Basis of Variegated Ly49A Gene Expression and Identification of a Critical Regulatory Element
Authors: Tanamachi Dawn M. , Moniot Deborah C. , Cado Dragana , Liu Scot D. , Hsia Jennifer K. , Raulet David H. 
Published: April 2014

Abstract
Several gene families are known in which member genes are expressed in variegated patterns in differentiated cell types. Mechanisms responsible for imposition of a variegated pattern of gene expression are unknown. Members of the closely linked Ly49 inhibitory receptor gene family are expressed in a variegated fashion by NK cells. Variegated expression of these genes results in subsets of NK cells that differ in specificity for MHC class I molecules. To address the mechanisms underlying variegation, a 30-kb genomic fragment containing a single Ly49 gene was used to generate a panel of murine transgenic lines. The results demonstrated that, in almost all of the lines, the isolated Ly49A gene was expressed in a variegated pattern, remarkably similar in nearly all respects to the expression pattern of the endogenous Ly49A gene. Furthermore, the developmental timing of gene expression and regulation by host MHC molecules closely mirrored that of the endogenous Ly49A gene. Therefore, Ly49 variegation does not require competition in cis between different Ly49 genes, and the sequences imposing variegation are located proximally to Ly49 genes. Efforts to define regulatory elements of the Ly49A gene led to the identification of a DNase I hypersensitive site 4.5 kb upstream of the Ly49A gene transcription initiation site, which was shown to be essential for transgene expression. Highly related sequence elements were found upstream of other Ly49 genes, suggesting that a similar regulatory element controls each Ly49 gene.
Polymorphisms in IL-4Rα Correlate with Airways Hyperreactivity, Eosinophilia, and Ym Protein Expression in Allergic IL-13−/− Mice
Authors: Webb Dianne C. , Matthaei Klaus I. , Cai Yeping , McKenzie Andrew N. J. , Foster Paul S. 
Published: April 2014

Abstract
The development of airways hyperreactivity in allergic IL-13−/− mice is controversial and appears to correlate with the number of times that the original 129 × C57BL/6 founder strain has been crossed to the BALB/c background. In this investigation, we compared allergic responses in founder IL-13−/− mice crossed for either 5 (N5) or 10 (N10) generations to BALB/c mice. Whereas allergic N5 IL-13−/− mice developed airways hyperreactivity, tissue eosinophilia, elevated IgE, and pulmonary expression of Ym proteins, these processes were attenuated in N5 IL-13−/− mice treated with an IL-4-neutralizing Ab, and in N10 IL-13−/− mice. These data showed that IL-4 was more effective in regulating allergic responses in N5 IL-13−/− mice than in N10 IL-13−/− mice. To elucidate the mechanism associated with these observations, we show by restriction and sequence analysis that N5 IL-13−/− mice express the C57BL/6 form of IL-4Rα and N10 IL-13−/− mice express the BALB/c form. Despite the near identical predicted molecular mass of these isoforms, IL-4Rα from N5 IL-13−/− mice migrates with a slower electrophoretic mobility than IL-4Rα from N10 IL-13−/− mice, suggesting more extensive posttranslational modification of the N5 form. The Thre49Ile polymorphism in the extracellular domain of BALB/c IL-4Rα has been demonstrated to disrupt N-linked glycosylation of Asn47 and increase the dissociation rate of the IL-4Rα/IL-4 interaction. Collectively, these data show that polymorphisms in IL-4Rα, which have been shown to affect the interaction with IL-4, correlate with the ability of IL-4 to regulate allergic responses in IL-13−/− mice.
T Cytotoxic-1 CD8+ T Cells Are Effector Cells against Pneumocystis in Mice
Authors: Mc Allister Florencia , Steele Chad , Zheng Mingquan , Young Erana , Shellito Judd E. , Marrero Luis , Kolls Jay K. 
Published: April 2014

Abstract
Host defenses are profoundly compromised in HIV-infected hosts due to progressive depletion of CD4+ T lymphocytes. A hallmark of HIV infection is Pneumocystis carinii (PC) pneumonia. Recently, CD8+ T cells, which are recruited to the lung in large numbers in response to PC infection, have been associated with some level of host defense as well as contributing to lung injury in BALB/c mice. In this study, we show that CD8+ T cells that have a T cytotoxic-1 response to PC in BALB/c mice, as determined by secretion of IFN-γ, have in vitro killing activity against PC and effect clearance of the organism in adoptive transfer studies. Moreover, non-T cytotoxic-1 CD8+ T cells lacked in vitro effector activity and contributed to lung injury upon adoptive transfer. This dichotomous response in CD8+ T cell response may in part explain the clinical heterogeneity in the severity of PC pneumonia.
IgE Enhances Parasite Clearance and Regulates Mast Cell Responses in Mice Infected with Trichinella spiralis
Authors: Gurish Michael F. , Bryce Paul J. , Tao Hong , Kisselgof Alison B. , Thornton Elizabeth M. , Miller Hugh R. , Friend Daniel S. , Oettgen Hans C. 
Published: April 2014

Abstract
Trichinella spiralis infection elicits a vigorous IgE response and pronounced intestinal and splenic mastocytosis in mice. Since IgE both activates mast cells (MC) and promotes their survival in culture, we examined its role in MC responses and parasite elimination in T. spiralis-infected mice. During primary infection, wild-type but not IgE-deficient (IgE−/−) BALB/c mice mounted a strong IgE response peaking 14 days into infection. The splenic mastocytosis observed in BALB/c mice following infection with T. spiralis was significantly diminished in IgE−/− mice while eosinophil responses were not diminished in either the blood or jejunum. Similar levels of peripheral blood eosinophilia and jejunal mastocytosis occurred in wild-type and IgE-deficient animals. Despite the normal MC response in the small intestine, serum levels of mouse MC protease-1 also were lower in parasite-infected IgE−/− animals and these animals were slower to eliminate the adult worms from the small intestine. The number of T. spiralis larvae present in the skeletal muscle of IgE−/− mice 28 days after primary infection was about twice that in BALB/c controls, and the fraction of larvae that was necrotic was reduced in the IgE-deficient animals. An intense deposition of IgE in and around the muscle larvae was observed in wild-type but not in IgE null mice. We conclude that IgE promotes parasite expulsion from the gut following T. spiralis infection and participates in the response to larval stages of the parasite. Furthermore, our observations support a role for IgE in the regulation of MC homeostasis in vivo.
The Role of SIGNR1 and the β-Glucan Receptor (Dectin-1) in the Nonopsonic Recognition of Yeast by Specific Macrophages
Authors: Taylor Philip R. , Brown Gordon D. , Herre Jurgen , Williams David L. , Willment Janet A. , Gordon Siamon 
Published: April 2014

Abstract
We recently demonstrated that the β-glucan receptor Dectin-1 (βGR) was the major nonopsonic β-glucan receptor on macrophages (Mφ) for the yeast-derived particle zymosan. However, on resident peritoneal Mφ, we identified an additional mannan-inhibitable receptor for zymosan that was distinct from the Mφ mannose receptor (MR). In this study, we have studied the mannose-binding potential of murine Mφ and identified the dendritic cell-specific ICAM-3-grabbing nonintegrin homolog, SIGN-related 1 (SIGNR1), as a major MR on murine resident peritoneal Mφ. Both SIGNR1 and βGR cooperated in the nonopsonic recognition of zymosan by these Mφ. When SIGNR1 was introduced into NIH3T3 fibroblasts or RAW 264.7 Mφ, it conferred marked zymosan-binding potential on these cells. However, in the nonprofessional phagocytes (NIH3T3), SIGNR1 was found to be poorly phagocytic, suggesting that other receptors such as βGR may play a more dominant role in particle internalization on professional phagocytes. Binding of zymosan to RAW 264.7 Mφ expressing SIGNR1 resulted in TNF-α production. Treatment of RAW 264.7 Mφ expressing SIGNR1, which express low levels of βGR, with β-glucans had little effect on binding or TNF-α production, indicating that there was no absolute requirement for βGR in this process. These studies have identified SIGNR1 as a major MR for fungal and other pathogens present on specific subsets of Mφ.
The Dendritic Cell Receptor DC-SIGN Discriminates among Species and Life Cycle Forms of Leishmania
Authors: Colmenares María , Corbí Angel L. , Turco Salvatore J. , Rivas Luis 
Published: April 2014

Abstract
Infection of dendritic cells by the human protozoal parasite Leishmania is part of its survival strategy. The dendritic cell receptors for Leishmania have not been established and might differ in their interactions among Leishmania species and infective stages. We present evidence that the surface C-type lectin DC-SIGN (CD 209) is a receptor for promastigote and amastigote infective stages from both visceral (Leishmania infantum) and New World cutaneous (Leishmania pifanoi) Leishmania species, but not for Leishmania major metacyclic promastigotes, an Old World species causing cutaneous leishmaniasis. Leishmania binding to DC-SIGN was found to be independent of lipophosphoglycan, the major glycoconjugate of the promastigote plasma membrane. Our findings emphasize the relevance of DC-SIGN in Leishmania-dendritic cell interactions, an essential link between innate and Leishmania-specific adaptive immune responses, and suggest that DC-SIGN might be a therapeutic target for both visceral and cutaneous leishmaniasis
Cutting Edge: Novel Priming of Tumor-Specific Immunity by NKG2D-Triggered NK Cell-Mediated Tumor Rejection and Th1-Independent CD4+ T Cell Pathway
Authors: Westwood Jennifer A. , Kelly Janice M. , Tanner Jane E. , Kershaw Michael H. , Smyth Mark J. , Hayakawa Yoshihiro 
Published: April 2014

Abstract
NKG2D is an activation receptor on NK cells and has been demonstrated as a primary cytotoxicity receptor for mouse NK cells. Primary rejection of class I-deficient RMA-S lymphoma cells expressing the NKG2D ligand, retinoic acid early inducible-1β, was critically dependent upon NK cell perforin and occurred independently of T cells. NKG2D-triggered NK cell rejection of RMA-S-retinoic acid early inducible-1β tumor primed a secondary tumor-specific T cell response mediated by both CD4+ and CD8+ T cells in the effector phase. Surprisingly, during the priming phase, CD4+ T cells, but not CD8+ T cells, were also required to generate this secondary T cell immunity; however, T cell priming was independent of Th1 cytokines, such as IFN-γ and IL-12. These data imply a novel pathway for priming T cell immunity, that is, stimulated upon NK cell-mediated cytotoxicity of NKG2D ligand-expressing tumor cells, dependent upon CD4+ T cells in the primary phase, and independent of conventional Th1-type immunity.
Enhanced Priming of Antigen-Specific CTLs In Vivo by Embryonic Stem Cell-Derived Dendritic Cells Expressing Chemokine Along with Antigenic Protein: Application to Antitumor Vaccination
Authors: Matsuyoshi Hidetake , Senju Satoru , Hirata Shinya , Yoshitake Yoshihiro , Uemura Yasushi , Nishimura Yasuharu 
Published: April 2014

Abstract
Dendritic cell (DC)-based immunotherapy is regarded as a promising means for anti-cancer therapy. The efficiency of T cell-priming in vivo by transferred DCs should depend on their encounter with T cells. In the present study, we attempted to improve the capacity of DCs to prime T cells in vivo by genetic modification to express chemokine with a T cell-attracting property. For genetic modification of DCs, we used a recently established method to generate DCs from mouse embryonic stem cells. We generated double-transfectant DCs expressing a chemokine along with a model Ag (OVA) by sequential transfection of embryonic stem cells, and then induced differentiation to DCs. We comparatively evaluated the effect of three kinds of chemokines; secondary lymphoid tissue chemokine (SLC), monokine induced by IFN-γ (Mig), and lymphotactin (Lptn). All three types of double transfectant DCs primed OVA-specific CTLs in vivo more efficiently than did DCs expressing only OVA, and the coexpression of SLC or Lptn was more effective than that of Mig. Immunization with DCs expressing OVA plus SLC or Mig provided protection from OVA-expressing tumor cells more potently than did immunization with OVA alone, and SLC was more effective than Mig. In contrast, coexpression of Lptn gave no additive effect on protection from the tumor. Collectively, among the three chemokines, expression of SLC was the most effective in enhancing antitumor immunity by transferred DCs in vivo. The findings provide useful information for the development of a potent DC-based cellular immunotherapy.
CD7 and CD28 Are Required for Murine CD4+CD25+ Regulatory T Cell Homeostasis and Prevention of Thyroiditis
Authors: Sempowski Gregory D. , Cross Scott J. , Heinly Craig S. , Scearce Richard M. , Haynes Barton F. 
Published: April 2014

Abstract
CD7 and CD28 are T cell Ig superfamily molecules that share common signaling mechanisms. To determine roles CD7 and CD28 might play in peripheral lymphocyte development and function, we have generated CD7/CD28-double-deficient mice. CD7- and CD28-single-deficient and CD7/CD28-double-deficient mice had normal levels of CD4 and CD8-single-positive T cells in thymus and spleen. However, CD28-deficient mice had decreased CD4+CD25+ T cells in spleen compared with wild-type mice, and CD7/CD28-double-deficient mice had decreased numbers of CD4+CD25+ T cells in both thymus and spleen compared with both wild-type and CD28-deficient mice. Functional studies demonstrated that CD4+CD25+ T cells from CD28-deficient and CD7/CD28-double-deficient mice could mediate suppression of CD3 mAb activation of CD4+CD25− wild-type T cells, but were less potent than wild-type CD4+CD25+ T regulatory cells. Thyroiditis developed in aged CD7/CD28-double-deficient mice (&gt;1 year) that was not seen in age-matched control mice or single CD7- or CD28-deficient mice, thus suggesting in vivo loss of T regulatory cells allowed for the development of spontaneous thyroiditis. Taken together, these data demonstrated collaborative roles for both CD7 and CD28 in determination of number and function of CD4+CD25+ T regulatory cells in the thymus and peripheral immune sites and in the development of spontaneous thyroiditis.
TCR-Independent and Caspase-Independent Apoptosis of Murine Thymocytes by CD24 Cross-Linking
Authors: Jung Kyeong Cheon , Park Weon Seo , Kim Hae Jung , Choi Eun Young , Kook Myeong-Cherl , Lee Han-Woong , Bae Youngmee 
Published: April 2014

AbstractCD24, also referred to as the heat-stable Ag, is a T cell differentiation Ag that is highly expressed on both CD4−CD8− double negative and CD4+CD8+ double positive thymocytes. Here, we report that CD24 ligation by a new anti-CD24 Ab, mT-20, induced the apoptosis of both double negative and double positive thymocytes, as well as the Scid.adh thymic lymphoma cell line, in the absence of TCR/CD3 engagement. CD24-mediated apoptosis of mouse thymocytes and its signaling pathway appeared not to be associated with p53, CD95, TNFR, or caspases. Furthermore, we found that cell death was blocked by the addition of scavengers of reactive oxygen species or by Bcl-2 overexpression, implying the role of CD24 signaling in the mitochondrial regulation. In this study, we suggest that CD24 ligation induced the apoptosis of immature thymocytes independently of both caspase and TCR.