bluuebunny/crossref_metadata_2025_split huggingface dataset:
Loss of IFN-γ Enables the Expansion of Autoreactive CD4+ T Cells to Induce Experimental Autoimmune Encephalomyelitis by a Nonencephalitogenic Myelin Variant Antigen
Authors: Sabatino Joseph J. , Shires John , Altman John D. , Ford Mandy L. , Evavold Brian D. 
Published: April 2014

AbstractMHC variant peptides are analogues of immunogenic peptides involving alterations of the MHC-binding residues, thereby altering the affinity of the peptide for the MHC molecule. Recently, our laboratory demonstrated that immunization of WT B6 mice with 45D, a low-affinity MHC variant peptide of MOG35–55, results in significantly attenuated experimental autoimmune encephalomyelitis (EAE), yet IFN-γ production is comparable to myelin oligodendrocyte glycoprotein (MOG)35–55-immunized mice. In light of these findings, we asked whether IFN-γ was required for the reduced encephalitogenicity of the weak ligand 45D in EAE. In this study, we report that immunization of mice deficient in IFN-γ or its receptor with 45D exhibit significant EAE signs compared with 45D-immunized wild-type B6 mice. Moreover, 45D-immunized IFN-γ−/− and IFN-γR−/− mice demonstrate MOG tetramer-positive CD4+ T cells within the CNS and display substantial numbers of MOG-specific CD4+ T cells in the periphery. In contrast, wild-type mice immunized with 45D exhibit reduced numbers of MOG-specific CD4+ T cells in the periphery and lack MOG tetramer- positive CD4+ T cells in the CNS. Importantly, the increased encephalitogenicity of 45D in mice lacking IFN-γ or IFN-γR was not due to deviation toward an enhanced IL-17-secreting phenotype. These findings demonstrate that IFN-γ significantly attenuates the encephalitogenicity of 45D and are the first to highlight the importance of IFN-γ signaling in setting the threshold level of responsiveness of autoreactive CD4+ T cells to weak ligands.
Brief Antigenic Stimulation Generates Effector CD8 T Cells with Low Cytotoxic Activity and High IL-2 Production
Authors: Usharauli David , Kamala Tirumalai 
Published: April 2014

Abstract
It is currently believed that a brief antigenic stimulation is sufficient to induce CD8 T cells to complete their differentiation program, become effector T cells, and subsequently generate memory. Because this concept was derived from studies in which only a single effector function was analyzed (either IFN-γ production or target cell lysis), we wondered whether monitoring for multiple effector functions might reveal novel characteristics of effector CD8 T cells elicited by brief or prolonged Ag exposure. Using an in vitro system to generate effector T cells and an in vivo adoptive transfer model to track donor CD8 T cells, we found that the differentiation programs acquired by CD8 T cells after brief or prolonged antigenic stimulation were different. Although the frequencies of IFN-γ and TNF-α producers were comparable for both effector CD8 T cell populations, there were major differences in cytotoxic potential and IL-2 production. Whereas prolonged (&gt;24 h) Ag exposure stimulated effector CD8 T cells with high cytotoxic activity and low IL-2 production, brief (&lt;24 h) stimulation generated effector CD8 T cells with low cytotoxic activity and high IL-2 production. The latter effector T cells rapidly converted into central memory-like CD8 T cells, exhibited long-term survival in adoptively transferred hosts, and gave robust recall responses upon Ag challenge. These data suggest that not all functions of effector CD8 T cells are equally inherited after brief or prolonged antigenic stimulation.
Assessment of Bet v 1-Specific CD4+ T Cell Responses in Allergic and Nonallergic Individuals Using MHC Class II Peptide Tetramers
Authors: Van Overtvelt Laurence , Wambre Erik , Maillère Bernard , von Hofe Eric , Louise Anne , Balazuc Anne Marie , Bohle Barbara , Ebo Didier , Leboulaire Christophe , Garcia Gilles , Moingeon Philippe 
Published: April 2014

Abstract
In this study, we used HLA-DRB1*0101, DRB1*0401, and DRB1*1501 peptide tetramers combined with cytokine surface capture assays to characterize CD4+ T cell responses against the immunodominant T cell epitope (peptide 141–155) from the major birch pollen allergen Bet v 1, in both healthy and allergic individuals. We could detect Bet v 1-specific T cells in the PBMC of 20 birch pollen allergic patients, but also in 9 of 9 healthy individuals tested. Analysis at a single-cell level revealed that allergen-specific CD4+ T cells from healthy individuals secrete IFN-γ and IL-10 in response to the allergen, whereas cells from allergic patients are bona fide Th2 cells (producing mostly IL-5, some IL-10, but no IFN-γ), as corroborated by patterns of cytokines produced by T cell clones. A fraction of Bet v 1-specific cells isolated from healthy, but not allergic, individuals also expresses CTLA-4, glucocorticoid-induced TNF receptor, and Foxp 3, indicating that they represent regulatory T cells. In this model of seasonal exposure to allergen, we also demonstrate the tremendous dynamics of T cell responses in both allergic and nonallergic individuals during the peak pollen season, with an expansion of Bet v 1-specific precursors from 10−6 to 10−3 among circulating CD4+ T lymphocytes. Allergy vaccines should be designed to recapitulate such naturally protective Th1/regulatory T cell responses observed in healthy individuals.
Human Cytomegalovirus Infection Induces a Rapid and Sustained Change in the Expression of NK Cell Receptors on CD8+ T Cells
Authors: van Stijn Amber , Rowshani Ajda T. , Yong Sila L. , Baas Frank , Roosnek Eddy , ten Berge Ineke J. M. , van Lier René A. W. 
Published: April 2014

Abstract
The CD8+ T cell compartment of human CMV-seropositive individuals characteristically contains a high proportion of cells that express NK cell receptors (NKRs) which may contribute to the surveillance of virus-infected cells. To test whether this enhanced expression is a direct and immediate result of CMV infection, we used DNA microarrays to analyze putative changes in the RNA expression level of 39 NKRs in CMV-specific CD8+ T cells of renal transplant recipients experiencing primary CMV infection. Already in the acute phase of infection 29 NKRs were induced, of which 19 remained high 1 year after cessation of viral replication. Activating and inhibitory NKRs were induced to a similar extent. Detailed longitudinal flow cytometric analyses confirmed NKR changes at the protein level. Strikingly, a strong induction of CD94 on CD3+ T cells was observed with surface expression of activating CD94dim NKG2C dimers appearing before inhibitory CD94bright NKG2A ones. After the acute phase of infection, the balance between inhibitory and activating receptors did not change. Thus, CMV infection induces a rapid and lasting change in the expression of NKRs on human CD8+ T cells.
Intracellular Retention of the NKG2D Ligand MHC Class I Chain-Related Gene A in Human Melanomas Confers Immune Privilege and Prevents NK Cell-Mediated Cytotoxicity
Authors: Fuertes Mercedes B. , Girart María V. , Molinero Luciana L. , Domaica Carolina I. , Rossi Lucas E. , Barrio María M. , Mordoh José , Rabinovich Gabriel A. , Zwirner Norberto W. 
Published: April 2014

Abstract
Most tumors grow in immunocompetent hosts despite expressing NKG2D ligands (NKG2DLs) such as the MHC class I chain-related genes A and B (MICA/B). However, their participation in tumor cell evasion is still not completely understood. Here we demonstrate that several human melanomas (cell lines and freshly isolated metastases) do not express MICA on the cell surface but have intracellular deposits of this NKG2DL. Susceptibility to NK cell-mediated cytotoxicity correlated with the ratio of NKG2DLs to HLA class I molecules but not with the amounts of MICA on the cell surface of tumor cells. Transfection-mediated overexpression of MICA restored cell surface expression and resulted in an increased in vitro cytotoxicity and IFN-γ secretion by human NK cells. In xenografted nude mice, these melanomas exhibited a delayed growth and extensive in vivo apoptosis. Retardation of tumor growth was due to NK cell-mediated antitumor activity against MICA-transfected tumors, given that this effect was not observed in NK cell-depleted mice. Also, mouse NK cells killed MICA-overexpressing melanomas in vitro. A mechanistic analysis revealed the retention of MICA in the endoplasmic reticulum, an effect that was associated with accumulation of endoH-sensitive (immature) forms of MICA, retrograde transport to the cytoplasm, and degradation by the proteasome. Our study identifies a novel strategy developed by melanoma cells to evade NK cell-mediated immune surveillance based on the intracellular sequestration of immature forms of MICA in the endoplasmic reticulum. Furthermore, this tumor immune escape strategy can be overcome by gene therapy approaches aimed at overexpressing MICA on tumor cells.
Villous B Cells of the Small Intestine Are Specialized for Invariant NK T Cell Dependence
Authors: Velázquez Peter , Wei Bo , McPherson Michael , Mendoza Lesley Marie A. , Nguyen Sandra L. , Turovskaya Olga , Kronenberg Mitchell , Huang Tiffany T. , Schrage Matthew , Lobato Lynn N. , Fujiwara Daisuke , Brewer Sarah , Arditi Moshe , Cheng Genhong , Sartor R. Balfour , Newberry Rodney D. , Braun Jonathan 
Published: April 2014

Abstract
B cells are important in mucosal microbial homeostasis through their well-known role in secretory IgA production and their emerging role in mucosal immunoregulation. Several specialized intraintestinal B cell compartments have been characterized, but the nature of conventional B cells in the lamina propria is poorly understood. In this study, we identify a B cell population predominantly composed of surface IgM+ IgD+ cells residing in villi of the small intestine and superficial lamina propria of the large intestine, but distinct from the intraepithelial compartment or organized intestinal lymphoid structures. Small intestinal (villous) B cells are diminished in genotypes that alter the strength of BCR signaling (Bruton tyrosine kinasexid, Gαi2−/−), and in mice lacking cognate BCR specificity. They are not dependent on enteric microbial sensing, because they are abundant in mice that are germfree or genetically deficient in TLR signaling. However, villous B cells are reduced in the absence of invariant NK T cells (Jα18−/− or CD1d−/− mice). These findings define a distinct population of conventional B cells in small intestinal villi, and suggest an immunologic link between CD1-restricted invariant NK T cells and this B cell population.
Developmental Control of Integrin Expression Regulates Th2 Effector Homing
Authors: Lee Seung-Hyo , Prince Joseph E. , Rais Muhammad , Kheradmand Farrah , Ballantyne Christie M. , Weitz-Schmidt Gabriele , Smith C. Wayne , Corry David B. 
Published: April 2014

AbstractIntegrin CD18, a component of the LFA-1 complex that also includes CD11a, is essential for Th2, but not Th1, cell homing, but the explanation for this phenomenon remains obscure. In this study, we investigate the mechanism by which Th2 effector responses require the LFA-1 complex. CD11a-deficient T cells showed normal in vitro differentiation and function. However, Th2 cell-dependent allergic lung disease was markedly reduced in CD11a null mice and wild-type mice given LFA-1 inhibitors, whereas control of infection with Leishmania major, a Th1-dependent response, was enhanced. In both disease models, recruitment of IL-4-, but not IFN-γ-secreting cells to relevant organs was impaired, as was adhesion of Th2 cells in vitro. These diverse findings were explained by the markedly reduced expression of CD29, an alternate homing integrin, on Th2, but not Th1, cells, which precludes Th2 homing in the absence of CD11a. Thus, murine Th1 and Th2 cells use distinct integrins for homing, suggesting novel opportunities for integrin-based therapeutic intervention in diverse human ailments influenced by Th2 cells.
TIM-4 Expressed on APCs Induces T Cell Expansion and Survival
Authors: Rodriguez-Manzanet Roselynn , Meyers Jennifer Hartt , Balasubramanian Savithri , Slavik Jacqueline , Kassam Nasim , Dardalhon Valerie , Greenfield Edward A. , Anderson Ana C. , Sobel Raymond A. , Hafler David A. , Strom Terry B. , Kuchroo Vijay K. 
Published: April 2014

Abstract
TIM (T cell, Ig, mucin) proteins can regulate T cell immune responses. Tim-4 mRNA is not expressed in T cells, but exclusively in APCs. Tim-4 is a ligand for Tim-1 and Tim-4.Ig fusion protein was shown to either inhibit or expand T cells. However, the molecular basis for such opposite effects was not defined. By generating mAbs, we show that expression of Tim-4 protein is restricted to CD11c+ and CD11b+ cells and is up-regulated upon activation. We show that Tim-4 specifically phosphorylates Tim-1 and induces T cell expansion by enhancing cell division and reducing apoptosis. Tim-4 also induces the phosphorylation of signaling molecules LAT, Akt, and ERK1/2 in T cells. Tim-4, expressed on APCs, is a costimulatory molecule that promotes T cell expansion and survival by cross-linking Tim-1 on T cells.
B Cell Receptor Basal Signaling Regulates Antigen-Induced Ig Light Chain Rearrangements
Authors: Schram Brian R. , Tze Lina E. , Ramsey Laura B. , Liu Jiabin , Najera Lydia , Vegoe Amanda L. , Hardy Richard R. , Hippen Keli L. , Farrar Michael A. , Behrens Timothy W. 
Published: April 2014

Abstract
BCR editing in the bone marrow contributes to B cell tolerance by orchestrating secondary Ig rearrangements in self-reactive B cells. We have recently shown that loss of the BCR or a pharmacologic blockade of BCR proximal signaling pathways results in a global “back-differentiation” response in which immature B cells down-regulate genes important for the mature B cell program and up-regulate genes characteristic of earlier stages of B cell development. These observations led us to test the hypothesis that self-Ag-induced down-regulation of the BCR, and not self-Ag-induced positive signals, lead to Rag induction and hence receptor editing. Supporting this hypothesis, we found that immature B cells from xid (x-linked immunodeficiency) mice induce re-expression of a Rag2-GFP bacterial artificial chromosome reporter as well as wild-type immature B cells following Ag incubation. Incubation of immature B cells with self-Ag leads to a striking reversal in differentiation to the pro-/pre-B stage of development, consistent with the idea that back-differentiation results in the reinduction of genes required for L chain rearrangement and receptor editing. Importantly, Rag induction, the back-differentiation response to Ag, and editing in immature and pre-B cells are inhibited by a combination of phorbol ester and calcium ionophore, agents that bypass proximal signaling pathways and mimic BCR signaling. Thus, mimicking positive BCR signals actually inhibits receptor editing. These findings support a model whereby Ag-induced receptor editing is inhibited by BCR basal signaling on developing B cells; BCR down-regulation removes this basal signal, thereby initiating receptor editing.
CD4+ T Lymphocytes Are Not Necessary for the Acute Rejection of Vascularized Mouse Lung Transplants
Authors: Gelman Andrew E. , Okazaki Mikio , Lai Jiaming , Kornfeld Christopher G. , Kreisel Friederike H. , Richardson Steven B. , Sugimoto Seiichiro , Tietjens Jeremy R. , Patterson G. Alexander , Krupnick Alexander S. , Kreisel Daniel 
Published: April 2014

AbstractAcute rejection continues to present a major obstacle to successful lung transplantation. Although CD4+ T lymphocytes are critical for the rejection of some solid organ grafts, the role of CD4+ T cells in the rejection of lung allografts is largely unknown. In this study, we demonstrate in a novel model of orthotopic vascularized mouse lung transplantation that acute rejection of lung allografts is independent of CD4+ T cell-mediated allorecognition pathways. CD4+ T cell-independent rejection occurs in the absence of donor-derived graft-resident hematopoietic APCs. Furthermore, blockade of the CD28/B7 costimulatory pathways attenuates acute lung allograft rejection in the absence of CD4+ T cells, but does not delay acute rejection when CD4+ T cells are present. Our results provide new mechanistic insight into the acute rejection of lung allografts and highlight the importance of identifying differences in pathways that regulate the rejection of various organs.
TLR-Activated B Cells Suppress T Cell-Mediated Autoimmunity
Authors: Lampropoulou Vicky , Hoehlig Kai , Roch Toralf , Neves Patricia , Gómez Elisabeth Calderón , Sweenie Claire H. , Hao Yi , Freitas Antonio A. , Steinhoff Ulrich , Anderton Stephen M. , Fillatreau Simon 
Published: April 2014

Abstract
TLR sense microbial infections, and control activation of immune responses. Dendritic cells, macrophages, and B lymphocytes express TLR and the TLR-signaling adaptor protein MyD88. The impact of TLR-activated B cells on T cell-mediated inflammation is unknown. In this study, we have used mice carrying B cell-restricted deficiencies in MyD88 or in distinct TLR to examine the impact of TLR-activated B cells on a T cell-mediated autoimmune disease, experimental autoimmune encephalomyelitis (EAE). We demonstrate that TLR-signaling in B cells suppresses inflammatory T cell responses (both Th1 and Th17), and stimulates recovery from EAE. Only certain TLR are required on B cells for resolution of EAE, and these are dispensable for disease initiation, indicating that a category of TLR agonists preferentially triggers a suppressive function in B cells and thereby limits autoimmune disease. The TLR agonists controlling the regulatory function of B cells are provided by components of Mycobacterium tuberculosis present in the adjuvant. Thus, MyD88 signaling in B cells antagonizes MyD88 signaling in other cells, which drives differentiation of Th17 cells and is required for induction of EAE. Altogether, our data indicate that B cells link recognition of microbial products via TLR to suppression of a T cell-mediated autoimmune disease.
TLR2-Dependent MyD88 Signaling Contributes to Early Host Defense in MurineEnterococcus faeciumPeritonitis
Authors: Leendertse Masja , Willems Rob J. L. , Giebelen Ida A. J. , van den Pangaart Petra S. , Wiersinga W. Joost , de Vos Alex F. , Florquin Sandrine , Bonten Marc J. M. , van der Poll Tom 
Published: April 2014

AbstractThe incidence of infections with Enterococcus faecium is increasing worldwide. TLRs have been implicated in the recognition of pathogens and the initiation of an adequate innate immune response. We here sought to determine the roles of MyD88, the common adaptor protein involved in TLR signaling, TLR2, TLR4, and CD14 in host defense against E. faecium peritonitis. MyD88 knockout (KO) mice demonstrated an impaired early response to E. faecium peritonitis, as reflected by higher bacterial loads in peritoneal fluid and liver accompanied by a markedly attenuated neutrophil influx into the abdominal cavity. In vitro, not only MyD88 KO macrophages but also TLR2 KO and CD14 KO macrophages displayed a reduced responsiveness to E. faecium. In accordance, transfection of TLR2 rendered human embryonic kidney 293 cells responsive to E. faecium, which was enhanced by cotransfection of CD14. TLR2 KO mice showed higher bacterial loads in peritoneal fluid after in vivo infection with E. faecium and a diminished influx of neutrophils, whereas CD14 KO mice had an unaltered host response. E. faecium phagocytosis and killing were not affected by MyD88, TLR2, or CD14 deficiency. TLR4 did not play a role in the immune response to E. faecium in vitro or in vivo. These data suggest that MyD88 contributes to the effective clearance of E. faecium during peritonitis at least in part via TLR2 and by facilitating neutrophil recruitment to the site of the infection.
Blockade of PD-1/B7-H1 Interaction Restores Effector CD8+ T Cell Responses in a Hepatitis C Virus Core Murine Model
Authors: Lukens John R. , Cruise Michael W. , Lassen Matthew G. , Hahn Young S. 
Published: April 2014

AbstractThe impaired function of CD8+ T cells is characteristic of hepatitis C virus (HCV) persistent infection. HCV core protein has been reported to inhibit CD8+ T cell responses. To determine the mechanism of the HCV core in suppressing Ag-specific CD8+ T cell responses, we generated a transgenic mouse, core(+) mice, where the expression of core protein is directed to the liver using the albumin promoter. Using a recombinant adenovirus to deliver Ag, we demonstrated that core(+) mice failed to clear adenovirus-LacZ (Ad-LacZ) infection in the liver. The effector function of LacZ-specific CD8+ T cells was particularly impaired in the livers of core(+) mice, with suppression of IFN-γ, TNF-α, and granzyme B production by CD8+ T cells. In addition, the impaired CD8+ T cell responses in core(+) mice were accompanied by the enhanced expression of the inhibitory receptor programmed death-1 (PD-1) by LacZ-specific CD8+ T cells and its ligand B7-H1 on liver dendritic cells following Ad-LacZ infection. Importantly, blockade of the PD-1/B7-H1 inhibitory pathway (using a B7-H1 blocking antibody) in core(+) mice enhanced effector function of CD8+ T cells and cleared Ad-LacZ-infection as compared with that in mice treated with control Ab. This suggests that the regulation of the PD-1/B7-H1 inhibitory pathway is crucial for HCV core-mediated impaired T cell responses and viral persistence in the liver. This also suggests that manipulation of the PD-1/B7-H1 pathway may be a potential immunotherapy to enhance effector T cell responses during persistent HCV infection.
Retargeting of Human T Cells to Tumor-Associated MUC1: The Evolution of a Chimeric Antigen Receptor
Authors: Wilkie Scott , Picco Gianfranco , Foster Julie , Davies David M. , Julien Sylvain , Cooper Lucienne , Arif Sefina , Mather Stephen J. , Taylor-Papadimitriou Joyce , Burchell Joy M. , Maher John 
Published: April 2014

AbstractMUC1 is a highly attractive immunotherapeutic target owing to increased expression, altered glycosylation, and loss of polarity in &gt;80% of human cancers. To exploit this, we have constructed a panel of chimeric Ag receptors (CAR) that bind selectively to tumor-associated MUC1. Two parameters proved crucial in optimizing the CAR ectodomain. First, we observed that the binding of CAR-grafted T cells to anchored MUC1 is subject to steric hindrance, independent of glycosylation status. This was overcome by insertion of the flexible and elongated hinge found in immunoglobulins of the IgD isotype. Second, CAR function was highly dependent upon strong binding capacity across a broad range of tumor-associated MUC1 glycoforms. This was realized by using an Ab-derived single-chain variable fragment (scFv) cloned from the HMFG2 hybridoma. To optimize CAR signaling, tripartite endodomains were constructed. Ultimately, this iterative design process yielded a potent receptor termed HOX that contains a fused CD28/OX40/CD3ζ endodomain. HOX-expressing T cells proliferate vigorously upon repeated encounter with soluble or membrane-associated MUC1, mediate production of proinflammatory cytokines (IFN-γ and IL-17), and elicit brisk killing of MUC1+ tumor cells. To test function in vivo, a tumor xenograft model was derived using MDA-MB-435 cells engineered to coexpress MUC1 and luciferase. Mice bearing an established tumor were treated i.p. with a single dose of engineered T cells. Compared with control mice, this treatment resulted in a significant delay in tumor growth as measured by serial bioluminescence imaging. Together, these data demonstrate for the first time that the near-ubiquitous MUC1 tumor Ag can be targeted using CAR-grafted T cells.