bluuebunny/crossref_metadata_2025_split huggingface dataset:
Increase in Hepatic NKT Cells in Leukocyte Cell-Derived Chemotaxin 2-Deficient Mice Contributes to Severe Concanavalin A-Induced Hepatitis
Authors: Saito Takeshi , Okumura Akinori , Watanabe Hisami , Asano Masahide , Ishida-Okawara Akiko , Sakagami Junko , Sudo Katsuko , Hatano-Yokoe Yoshimi , Bezbradica Jelena S. , Joyce Sebastian , Abo Toru , Iwakura Yoichiro , Suzuki Kazuo , Yamagoe Satoshi 
Published: April 2014

Abstract
Leukocyte cell-derived chemotaxin 2 (LECT2) was originally identified for its possible chemotactic activity against human neutrophils in vitro. It is a 16-kDa protein that is preferentially expressed in the liver. Its homologues have been widely identified in many vertebrates. Current evidence suggests that LECT2 may be a multifunctional protein like cytokines. However, the function of LECT2 in vivo remains unclear. To elucidate the role of this protein in vivo, we have generated LECT2-deficient (LECT2−/−) mice. We found that the proportion of NKT cells in the liver increased significantly in LECT2−/− mice, although those of conventional T cells, NK cells, and other cell types were comparable with those in wild-type mice. Consistent with increased hepatic NKT cell number, the production of IL-4 and IFN-γ was augmented in LECT2−/− mice upon stimulation with α-galactosylceramide, which specifically activates Vα14 NKT cells. In addition, NKT cell-mediated cytotoxic activity against syngeneic thymocytes increased in hepatic mononuclear cells obtained from LECT2−/− mice in vitro. Interestingly, the hepatic injury was exacerbated in LECT2−/− mice upon treatment with Con A, possibly because of the significantly higher expression of IL-4 and Fas ligand. These results suggest that LECT2 might regulate the homeostasis of NKT cells in the liver and might be involved in the pathogenesis of hepatitis.
A Structurally Available Encephalitogenic Epitope of Myelin Oligodendrocyte Glycoprotein Specifically Induces a Diversified Pathogenic Autoimmune Response
Authors: Bischof Felix , Bins Adriaan , Dürr Michael , Zevering Yinka , Melms Arthur , Kruisbeek Ada M. 
Published: April 2014

Abstract
Multiple sclerosis is an inflammatory disease of the CNS that involves immune reactivity against myelin oligodendrocyte glycoprotein (MOG), a type I transmembrane protein located at the outer surface of CNS myelin. The epitope MOG92–106 is a DR4-restricted Th cell epitope and a target for demyelinating autoantibodies. In this study, we show that the immune response elicited by immunization with this epitope is qualitatively different from immune responses induced by the well-defined epitopes myelin basic protein (MBP) 84–96 and proteolipid protein (PLP) 139–151. Mice with MOG92–106-, but not with MBP84–96- or PLP139–151-induced experimental autoimmune encephalomyelitis developed extensive B cell reactivity against secondary myelin Ags. These secondary Abs were directed against a set of encephalitogenic peptide Ags derived from MBP and PLP as well as a broad range of epitopes spanning the complete MBP sequence. The observed diversification of the B cell reactivity represents a simultaneous spread toward a broad range of antigenic epitopes and differs markedly from T cell epitope spreading that follows a sequential cascade. The Abs were of the isotypes IgG1 and IgG2b, indicating that endogenously recruited B cells receive help from activated T cells. In sharp contrast, B cell reactivity in MBP84–96- and PLP139–151-induced experimental autoimmune encephalomyelitis was directed against the disease-inducing Ag only. These data provide direct evidence that the nature of the endogenously acquired immune reactivity during organ-specific autoimmunity critically depends on the disease-inducing Ag. They further demonstrate that the epitope MOG92–106 has the specific capacity to induce a widespread autoimmune response.
Regulation of Cockroach Antigen-Induced Allergic Airway Hyperreactivity by the CXCR3 Ligand CXCL9
Authors: Thomas Molly S. , Kunkel Steven L. , Lukacs Nicholas W. 
Published: April 2014

AbstractAllergic airway disease is characterized by a robust lymphocytic infiltrate, elaboration of Th2-type inflammatory mediators, pulmonary eosinophil accumulation, and airway hyperreactivity. The CXCR3 ligands, CXCL9 (monokine induced by IFN-γ) and CXCL10 (IFN-inducible protein, 10 kDa), are IFN-γ-inducible, Th1-type chemokines. As CXCL10 has been previously shown to participate in the modulation of allergic inflammation, we were interested in investigating the possible role that CXCL9 may play in this inflammatory response. Expression of CXCL9 was primarily identified in airway epithelial cells by immunohistochemical staining. Airway neutralization of CXCL9 at the time of allergen challenge significantly increased airway hyperreactivity, airway eosinophil accumulation, and IL-4 levels in the bronchoalveolar lavage while significantly decreasing airway levels of IL-12. In contrast, introduction of exogenous CXCL9 into the airway at the time of allergen challenge dramatically reduced airway hyper-reactivity and eosinophil accumulation. Moreover, pulmonary levels of IL-4 were significantly reduced, whereas levels of IL-12 were significantly increased, with exogenous CXCL9 treatment. In lymphocytes restimulated with CXCL9 and allergen in vitro, CXCL9 down-regulated IL-4 expression and up-regulated IFN-γ expression, suggesting that CXCL9 is able to direct activated lymphocytes toward a Th1-type phenotype. Additionally, CXCL9 was shown to inhibit CC chemokine ligand 11-induced eosinophil chemotaxis in in vitro assays. Taken together, our results demonstrate that the CXCR3 ligand CXCL9 is involved in regulation of the allergic response in the lung by regulation of lymphocyte activation and eosinophil recruitment.
Requirement for CD28 in the Effector Phase of Allergic Airway Inflammation
Authors: Kimzey Stephanie L. , Liu Pingfan , Green Jonathan M. 
Published: April 2014

AbstractCentral to the pathogenesis of allergic airway inflammation are the activation and differentiation of T lymphocytes. This process requires the participation of the CD28 costimulatory receptor. Blockade of CD28 has been demonstrated to prevent inflammation and airway hyperreactivity in a murine model of asthma. Whether this is due specifically to defects in initial T cell activation or whether effector responses are also impaired has not been determined. Using adoptive transfer studies of Ag-specific lymphocytes, we demonstrate that CD28 has a critical role in both the induction and effector phase of allergic airway inflammation. Transfer of in vitro activated and Th2-differentiated Ag-specific lymphocytes from wild-type hosts restored inflammation, but not tissue eosinophilia in CD28-deficient recipients. Furthermore, similarly activated and differentiated CD28-deficient lymphocytes were ineffective at mediating inflammation in wild-type recipients. Secondary cytokine and proliferative responses of activated Th2 cells were highly dependent on CD28 in vitro. Moreover, eosinophil recruitment to both the lung and peritoneum is impaired by the lack of CD28, suggesting a generalized defect in the ability of eosinophils to accumulate at sites of inflammation in vivo. These data identify a novel role for CD28 in the effector phase of allergic airway inflammation and suggest that inhibition of this pathway may be a useful therapeutic intervention in previously sensitized individuals.
Comparative Analysis of the CD19+ and CD138+ Cell Antibody Repertoires in the Cerebrospinal Fluid of Patients with Multiple Sclerosis
Authors: Ritchie Alanna M. , Gilden Donald H. , Williamson R. Anthony , Burgoon Mark P. , Yu Xiaoli , Helm Karen , Corboy John R. , Owens Gregory P. 
Published: April 2014

Abstract
Increased amounts of intrathecally synthesized IgG and oligoclonal bands have long been recognized as a hallmark of multiple sclerosis (MS). B cells and plasma cells are components of the inflammatory infiltrates in both active and chronic MS lesions, and increased numbers of these cells are present in MS cerebrospinal fluid (CSF). Single-cell RT-PCR was used to analyze both the CD19+ B cell and CD138+ plasma cell populations in CSF of two patients with clinically definite MS and of one MS patient whose CSF was obtained after a clinically isolated syndrome, but before the second episode. Sequence analysis of amplified IgG V region sequences identified the rearranged germline segments, extent of somatic mutation, and clonal relationships within and between the two cell populations in the three MS patients. Expanded B cell and plasma cell clones were detected in each MS CSF and in all three patients the CD138+ IgG repertoire was more restricted. However, little if any significant sequence overlap was observed between the CD19+ and CD138+ repertoires of each donor. Detection of plasma cell clones by single-cell PCR will facilitate the in vitro production of recombinant Abs useful in identifying disease-relevant Ags.
γδ T Cells Enhance the Expression of Experimental Autoimmune Encephalomyelitis by Promoting Antigen Presentation and IL-12 Production
Authors: Odyniec Artur , Szczepanik Marian , Mycko Marcin P. , Stasiolek Mariusz , Raine Cedric S. , Selmaj Krzysztof W. 
Published: April 2014

Abstract
Using an adoptive transfer model of experimental autoimmune encephalomyelitis (EAE) induced by myelin basic protein (MBP)-reactive lymph node cells (LNC), we have shown that depletion of γδ T cells from LNC resulted in diminished severity of EAE in recipient mice, both clinically and histopathologically. The reduced potency of γδ T cell-depleted LNC to induce EAE correlated with decreased cell proliferation in response to MBP. The γδ T cell effect upon the threshold of MBP-induced LNC proliferation and EAE transfer was restored by reconstitution of γδ T cells derived from either MBP-immunized or naive mice, indicating that this effect was not Ag specific. The enhancing effect of γδ T cells on MBP-induced proliferation and EAE transfer required direct cell-to-cell contact with LNC. The γδ T cell effect upon the LNC response to MBP did not involve a change in expression of the costimulatory molecules CD28, CD40L, and CTLA-4 on TCRαβ+ cells, and CD40, CD80, and CD86 on CD19+ and CD11b+ cells. However, depletion of γδ T cells resulted in significant reduction in IL-12 production by LNC. That γδ T cells enhanced the MBP response and severity of adoptive EAE by stimulating IL-12 production was supported by experiments showing that reconstitution of the γδ T cell population restored IL-12 production, and that γδ T cell depletion-induced effects were reversed by the addition of IL-12. These results suggest a role for γδ T cells in the early effector phase of the immune response in EAE.
The Gene Related to Anergy in Lymphocytes, an E3 Ubiquitin Ligase, Is Necessary for Anergy Induction in CD4 T Cells
Authors: Seroogy Christine M. , Soares Luis , Ranheim Erik A. , Su Leon , Holness Claire , Bloom Debra , Fathman C. Garrison 
Published: April 2014

Abstract
Acquisition of the anergy phenotype in T cells is blocked by inhibitors of protein synthesis and calcineurin activity, suggesting that anergic T cells may have a unique genetic program. Retroviral transduction of hemopoietic stem cells from TCR transgenic mice and subsequent reconstitution of syngeneic mice to express the E3 ubiquitin ligase, gene related to anergy in lymphocytes (GRAIL), or an enzymatically inactive form, H2N2 GRAIL, allowed analysis of the role of GRAIL in T cell anergy in vivo. Constitutive expression of GRAIL was sufficient to render naive CD4 T cells anergic, however, when the enzymatically inactive form H2N2 GRAIL was expressed, it functioned as a dominant negative of endogenous GRAIL and blocked the development of anergy. These data provide direct evidence that a biochemical pathway composed of GRAIL and/or GRAIL-interacting proteins is important in the development of the CD4 T cell anergic phenotype in vivo.
Cutting Edge: Cross-Presentation of Cell-Associated Antigens to MHC Class I Molecule Is Regulated by a Major Transcription Factor for Heat Shock Proteins
Authors: Zheng Hong , Li Zihai 
Published: April 2014

Abstract
The ability for the professional APC to cross-present Ag to MHC class I from parenchymal cells is essential for priming as well as tolerance of CD8+ T cells against intracellular Ags. Since cross-presentations of non-cell-associated free Ags are inefficient, the roles of molecular chaperones or heat shock proteins (HSPs) in chaperoning Ags to APCs have been postulated. We herein genetically addressed this hypothesis using mice that were defective of heat shock factor 1 (Hsf1), a major transcription factor for HSPs. Hsf1−/− mice have a decreased expression of several HSPs including HSP90 and HSP70. Using multiple Ag systems, we demonstrated that cross-priming of Ag-specific CD8+ T cells was inefficient when Ag expression was restricted to Hsf1−/− non-APCs. Our study provides the first genetic evidence for the roles of Hsf1 in regulating cross-presentation of MHC class I-associated Ags.
CD63 as an Activation-Linked T Cell Costimulatory Element
Authors: Pfistershammer Katharina , Majdic Otto , Stöckl Johannes , Zlabinger Gerhard , Kirchberger Stefanie , Steinberger Peter , Knapp Walter 
Published: April 2014

AbstractDendritic cells (DC) are unique in their capacity to either stimulate or regulate T cells, and receptor/ligand pairs on DC and T cells are critically involved in this process. In this study we present such a molecule, which was discovered by us when analyzing the functional effects of an anti-DC mAb. This mAb, 11C9, reacted strongly with DC, but only minimally with lymphocytes. In MLR it constantly reduced DC-induced T cell activation. Therefore, we assumed that mAb 11C9 primarily exerts its functions by binding to a DC-structure. This does not seem to be the case, however. Preincubation of DC with mAb 11C9 before adding T cells had no inhibitory effect on T cell responses. Retroviral expression cloning identified the 11C9 Ag as CD63. This lysosomal-associated membrane protein (LAMP-3), is only minimally expressed on resting T cells but can, as we show, quickly shift to the surface upon stimulation. Cross-linkage of that structure together with TCR-triggering induces strong T cell activation. CD63 on T cells thus represents an alternative target for mAb 11C9 with its binding to activated T cells rather than DC being responsible for the observed functional effects. This efficient CD63-mediated costimulation of T cells is characterized by pronounced induction of proliferation, strong IL-2 production and compared with CD28 enhanced T cell responsiveness to restimulation. Particularly in this latter quality CD63 clearly surpasses several other CD28-independent costimulatory pathways previously described. CD63 thus represents an activation-induced reinforcing element, whose triggering promotes sustained and efficient T cell activation and expansion.
The Role of B Cell-Mediated T Cell Costimulation in the Efficacy of the T Cell Retargeting Bispecific Antibody BIS20x3
Authors: Stel Alja J. , Kroesen Bart-Jan , Jacobs Susan , Groen Herman , de Leij Lou F. M. H. , Kluin-Nelemans Hanneke C. , Withoff Sebo 
Published: April 2014

Abstract
In this study, we investigated the role of the naturally occurring B cell-mediated T cell costimulation in the antitumor efficacy of the bispecific Ab BIS20x3. BIS20x3 has a dual specificity for both CD20 and CD3 and has previously been shown to effectively direct the lytic potential of cytolytic T cells toward malignant, CD20+ B cells. BIS20x3 instigated T cell-B cell interaction caused a dose-dependent activation of T cells that was 30 times stronger when compared with T cell activation induced by monovalent anti-CD3 Abs. The activation of T cells by BIS20x3 and B cells appeared functional and resulted in the rapid induction of high lytic potential in freshly isolated peripheral T cells. BIS20x3-mediated T cell-B cell interaction resulted in a significant up-regulation of ICAM-1 on B cells and the activation of T cells was found to be dependent on the interaction of ICAM-1 with LFA-1 and trans-activation by the NF-κB pathway. Also, the lytic potential of freshly isolated T cells activated via BIS20x3 appeared to be dependent on NF-κB signaling in the target B cells. Interestingly, the costimulatory signaling effects described in this study appeared specifically related to the targeting against CD20 because targeting against CD19, by a CD3xCD19-directed bispecific Ab, was significantly less effective in inducing T cell activation and T cell-mediated B cell lysis. Together these results demonstrate that the malignant B cells actively contribute to their own demise upon CD20-directed bispecific Ab-mediated T cell targeting.
Mechanisms of Peritoneal B-1a Cells Accumulation Induced by Murine Lupus Susceptibility LocusSle2
Authors: Xu Zhiwei , Butfiloski Edward J. , Sobel Eric S. , Morel Laurence 
Published: April 2014

AbstractThe abundance of B-1a cells found in the peritoneal cavity of mice is under genetic control. The lupus-prone mouse New Zealand Black and New Zealand White (NZB × NZW)F1 and its derivative NZM2410 are among the strains with the highest numbers of peritoneal B1-a cells. We have previously identified an NZM2410 genetic locus, Sle2, which is associated with the production of large numbers of B-1a cells. In this paper, we examined the mechanisms responsible for this phenotype by comparing congenic C57BL/6 mice with or without Sle2. Fetal livers generated more B-1a cells in B6.Sle2 mice, providing them with a greater starting number of B-1a cells early in life. Sle2-expressing B1-a cells proliferated significantly more in vivo than their B6 counterparts, and reciprocal adoptive transfers showed that this phenotype is intrinsic to Sle2 peritoneal B cells. The rate of apoptosis detected was significantly lower in B6.Sle2 peritoneal cavity B-1a cells than in B6, with or without exogenous B cell receptor cross-linking. Increased proliferation and decreased apoptosis did not affect Sle2 peritoneal B-2 cells. In addition, a significant number of peritoneal cavity B-1a cells were recovered in lethally irradiated B6.Sle2 mice reconstituted with B6.Igha bone marrow, showing radiation resistance in Sle2 B-1a cells or its precursors. Finally, B6.Sle2 adult bone marrow and spleen were a significant source of peritoneal B-1a cells when transferred into B6.Rag2−/− mice. This suggests that peritoneal B-1a cells are replenished throughout the animal life span in B6.Sle2 mice. These results show that Sle2 regulates the size of the B-1a cell compartment at multiple developmental checkpoints.
Homeostatic Proliferation of a Qa-1b-Restricted T Cell: A Distinction between the Ligands Required for Positive Selection and for Proliferation in Lymphopenic Hosts
Authors: Sullivan Barbara A. , Reed-Loisel Lisa M. , Kersh Gilbert J. , Jensen Peter E. 
Published: April 2014

Abstract
Naive T cells proliferate in response to self MHC molecules after transfer into lymphopenic hosts, a process that has been termed homeostatic proliferation (HP). Previous studies have demonstrated that HP is driven by low level signaling induced by interactions with the same MHC molecules responsible for positive selection in the thymus. Little is known about the homeostatic regulation of T cells specific for class Ib molecules, including Qa-1 and H2-M3, though it has been suggested that their capacity to undergo homeostatic expansion may be inherently limited. In this study, we demonstrate that naive 6C5 TCR transgenic T cells with specificity for Qa-1b have a capacity similar to conventional T cells to undergo HP after transfer into sublethally irradiated mice. Proliferation was largely dependent on the expression of β2-microglobulin, and experiments with congenic recipients expressing Qa-1a instead of Qa-1b demonstrated that HP is specifically driven by Qa-1b and not through cross-recognition of classical class I molecules. Thus, the same MHC molecule that mediates positive selection of 6C5 T cells is also required for HP. Homeostatic expansion, like positive selection, occurs in the absence of a Qa-1 determinant modifier, the dominant self-peptide bound to Qa-1 molecules. However, experiments with TAP−/− recipients demonstrate a clear distinction between the ligand requirements for thymic selection and HP. Positive selection of 6C5 T cells is dependent on TAP function, thus selection is presumably mediated by TAP-dependent peptides. By contrast, HP occurs in TAP−/− recipients, providing an example where the ligand requirements for HP are less stringent than for thymic selection.
Negative Regulation of NK Cell Activities by Inhibitory Receptor CD94/NKG2A Leads to Altered NK Cell-Induced Modulation of Dendritic Cell Functions in Chronic Hepatitis C Virus Infection
Authors: Jinushi Masahisa , Takehara Tetsuo , Tatsumi Tomohide , Kanto Tatsuya , Miyagi Takuya , Suzuki Takahiro , Kanazawa Yoshiyuki , Hiramatsu Naoki , Hayashi Norio 
Published: April 2014

Abstract
NK cells are potent activators of dendritic cells (DCs), but it remains obscure how third-party cells affect the ability of NK cells to modulate DC functions. We show here that NK cells derived from healthy donors (N-NK), when cocultured with human liver epithelial cells, induced maturation as well as activation of DCs, such as increased migratory capacity as well as T cell stimulatory activity. In contrast, NK cells from chronic hepatitis C virus-infected donors (HCV-NK) were not capable of activating DCs under the same conditions. In comparison to N-NK, HCV-NK showed higher expression of CD94/NKG2A and produced IL-10 and TGFβ when cultured with hepatic cells, most of which express HLA-E, a ligand for CD94/NKG2A. Blockade of NKG2A restored the ability of HCV-NK to activate DCs, which appeared to result from the reduced NK cell production of IL-10 and TGFβ. The blockade also endowed HCV-NK with an ability to drive DCs to generate Th1-polarized CD4+ T cells. These findings show that NK cell modulation of DCs is regulated by third-party cells through NK receptor and its ligand interaction. Aberrant expression of NK receptors may have an impact on the magnitude and direction of DC activation of T cells under pathological conditions, such as chronic viral infection.
Expression and Characterization of a Novel CD6 Ligand in Cells Derived from Joint and Epithelial Tissues
Authors: Saifullah Mohammad K. , Fox David A. , Sarkar Sujata , Abidi Syed M. A. , Endres Judith , Piktel Joseph , Haqqi Tariq M. , Singer Nora G. 
Published: April 2014

Abstract
CD6 is a T cell surface glycoprotein that plays an important role in interactions of thymocytes with thymic epithelial cells and in mature T cell interactions with selected nonprofessional tissue APCs. We describe a novel CD6 ligand (CD6L) 3A11 Ag that is distinct from the known CD6L (CD166). The 3A11 protein is expressed on cells derived from human thymus, skin, synovium, and cartilage, and its expression is enhanced by IFN-γ. mAbs directed against the 3A11 Ag and CD166 exhibit distinct patterns of binding to a panel of cell lines. Confocal microscopy shows that both CD166 and the 3A11 Ag are expressed at the cell surface, and that these proteins colocalize. The 3A11 Ag has a molecular mass of 130 kDa and is immunoprecipitated using either mAb 3A11 or soluble CD6-Ig fusion protein. mAbs directed against individual CD6L were less potent than was soluble CD6-Ig fusion protein in reducing adhesion of T cells to adherent 3A11-positive epithelial cells in vitro, suggesting that these Abs recognize epitopes on the 3A11 Ag and CD166 that are distinct from CD6 binding sites. Finally, transfection of epithelial cells with CD166-specific small interfering RNAs significantly decreased CD166 expression without alteration in 3A11 Ag levels, and thus confirmed that these two CD6L are distinct. Taken together, our data identifies a novel 130-kDa CD6L that may mediate interactions of synovial and epithelial cells with T lymphocytes.