bluuebunny/crossref_metadata_2025_split huggingface dataset:
CD40-Mediated Signal Transduction in Human Airway Smooth Muscle
Authors: Lazaar Aili L. , Amrani Yassine , Hsu Jason , Panettieri Reynold A. , Fanslow William C. , Albelda Steven M. , Puré Ellen 
Published: December 2022

AbstractCD40 is a member of the TNF receptor family that was initially described on the surface of B cells. Recently, CD40 has also been described on mesenchymal cells, such as endothelial cells and fibroblasts, where engagement by its ligand CD40 ligand can lead to up-regulation of costimulatory and cell adhesion molecules, as well as secretion of proinflammatory cytokines. Since airway inflammation potentially involves cell-cell interactions of T cells and eosinophils (which express CD40 ligand) with airway smooth muscle (ASM) cells, we postulated that ASM may express CD40 and that engagement of ASM CD40 may modulate smooth muscle cell function. We demonstrate that CD40 is expressed on cultured human ASM and that expression can be increased by treatment with TNF-α or IFN-γ. Cross-linking CD40 on ASM resulted in enhanced IL-6 secretion and an increase in intracellular calcium concentrations, which were dependent on calcium influx. We show that CD40-mediated signaling events include protein tyrosine phosphorylation and activation of NF-κB. Pretreatment of ASM with the tyrosine kinase inhibitors genistein or herbimycin inhibited the rapid mobilization of calcium induced via CD40, suggesting that calcium mobilization was coupled to activation of protein tyrosine kinases. In addition, inhibition of calcium influx inhibited both CD40-mediated NF-κB activation and enhancement of IL-6 secretion. These results delineate a potentially important CD40-mediated signal-transduction pathway in ASM, involving protein tyrosine kinase-dependent calcium mobilization, NF-κB activation, and IL-6 production. Together, these results suggest a mechanism whereby T cell/smooth muscle cell interactions may potentiate airway inflammation.
Th2-Induced Eotaxin Expression and Eosinophilia Coexist with Th1 Responses at the Effector Stage of Lung Inflammation
Authors: Li Li , Xia Yiyang , Nguyen Andrea , Feng Lili , Lo David 
Published: December 2022

AbstractThe T cell-mediated lung inflammation that is associated with allergic asthma is characterized mainly by massive eosinophil infiltration, which induces airway injury and the subsequent late-phase reactivity. Because Th2 cells are often isolated from asthmatic subjects, these cells are postulated to play a role in asthma pathogenesis. We report that adoptively transferred, influenza hemagglutinin-specific Th1 and Th2 cells induced different patterns of chemokines leading to different types of cellular infiltration. Th2 cells were sufficient to induce dramatic Ag-dependent lung eosinophilia and eotaxin expression; by contrast, Th1 transfer primarily induced neutrophil recruitment with little eotaxin production. To determine whether Th1 cells show inhibitory effects on Th2 cell-mediated responses, Th1 and Th2 cells were cotransferred. Hemagglutinin-specific Th1 cells did not inhibit Ag-induced lung eosinophilia, nor did they inhibit eotaxin expression. Furthermore, influenza virus infection of the lung in mice receiving hemagglutinin-specific Th2 cells also induced eotaxin expression and eosinophilia that could not be inhibited by the cotransfer of Th1 cells. Our results show that Th2-mediated allergic lung inflammation coexists with the Th1-mediated responses that are stimulated by diverse forms of Ags.
IL-12, But Not IFN-γ, Plays a Major Role in Sustaining the Chronic Phase of Colitis in IL-10-Deficient Mice
Authors: Davidson Natalie J. , Hudak Susan A. , Lesley Robin E. , Menon Satish , Leach Michael W. , Rennick Donna M. 
Published: December 2022

AbstractIL-10-deficient (IL-10−/−) mice develop chronic enterocolitis mediated by CD4+ Th1 cells producing IFN-γ. Because IL-12 can promote Th1 development and IFN-γ production, the ability of neutralizing anti-IL-12 mAb to modulate colitis in IL-10−/− mice was investigated. Anti-IL-12 mAb treatment completely prevented disease development in young IL-10−/− mice. Treatment of adult mice resulted in significant amelioration of established disease accompanied by reduced numbers of mesenteric lymph node and colonic CD4+ T cells and of mesenteric lymph node T cells spontaneously producing IFN-γ. In contrast, anti-IFN-γ mAb had minimal effect on disease reversal, despite a significant preventative effect in young mice. These findings suggested that IL-12 sustains colitis by supporting the expansion of differentiated Th1 cells that mediate disease independently of their IFN-γ production. This conclusion was supported by the finding that anti-IL-12 mAb greatly diminished the ability of a limited number of CD4+ T cells expressing high levels of CD45RB from diseased IL-10−/− mice to expand and cause colitis in recombination-activating gene-2−/− recipients, while anti-IFN-γ mAb had no effect. Furthermore, IL-12 could support pathogenic IL-10−/− T cells stimulated in vitro in the absence of IL-2. While these studies show that IL-12 plays an important role in sustaining activated Th1 cells during the chronic phase of disease, the inability of anti-IL-12 mAb to abolish established colitis or completely prevent disease transfer by Th1 cells suggests that additional factors contribute to disease maintenance.
Expression of Chemokine Receptors CXCR4 and CCR5 in HIV-1-Infected and Uninfected Individuals
Authors: Ostrowski Mario A. , Justement Shawn J. , Catanzaro Andrew , Hallahan Claire A. , Ehler Linda A. , Mizell Stephanie B. , Kumar Princy N. , Mican Jo Ann , Chun Tae-Wook , Fauci Anthony S. 
Published: December 2022

Abstract
The chemokine receptors CXCR4 and CCR5 have been identified as major coreceptors for HIV-1 entry into CD4+ T cells. The majority of primary HIV-1 isolates in early disease use CCR5 as a coreceptor, whereas during disease progression with the emergence of syncytium-inducing viruses, CXCR4 is also used. We performed a cross-sectional study in which we evaluated the expression of two HIV-1 coreceptors, CCR5 and CXCR4, in whole blood samples taken from HIV-1-infected and uninfected individuals. We demonstrate that CXCR4 on CD4+ and CD8+ T cells, and CD14+ monocytes is significantly down-regulated, and CCR5 expression on CD4+ T cells is up-regulated in HIV-infected individuals compared with uninfected controls. Coreceptor expression correlated with the level of cellular activation in vivo in both HIV-infected and uninfected individuals, with CXCR4 being expressed predominantly on quiescent (HLA-DR−) T cells and CCR5 being expressed predominantly on activated (HLA-DR+) T cells. Lower expression of CXCR4 and higher expression of CCR5 on CD4+ T cells correlated with advancing disease. In addition, a tendency for greater activation of CXCR4+CD4+ T cells in patients with advanced disease was observed. Patients who harbored syncytium-inducing viruses, however, could not be distinguished from those who harbored nonsyncytium-inducing viruses based on the level of CD4+ T cell activation or chemokine receptor expression.
Cutting Edge: Presence of Progenitors Restricted to T, B, or Myeloid Lineage, but Absence of Multipotent Stem Cells, in the Murine Fetal Thymus
Authors: Kawamoto Hiroshi , Ohmura Koichiro , Katsura Yoshimoto 
Published: December 2022

AbstractThe most immature population of fetal thymus (FT) cells has been shown to generate not only T but also B and myeloid cells. The present study was undertaken to clarify whether such a multipotent activity of the earliest population of FT cells is attributed to multipotent hemopoietic progenitors or to a mixture of lineage-restricted progenitors. Examination of individual FT progenitors by a recently established clonal assay system, which is able to determine the developmental potential of each progenitor toward T, B, and myeloid lineages, elucidated that a large majority of progenitors in FT were restricted to the T cell lineage. Presence of a small number of B or myeloid lineage-restricted progenitors was also disclosed. No multipotent progenitors, however, were detected in FT. These results are consistent with our recent finding that restriction of hemopoietic stem cells to T, B, and myeloid lineages takes place in the fetal liver.
Cutting Edge: Negative Regulation of Human T Cell Activation by the Receptor-Type Protein Tyrosine Phosphatase CD148
Authors: Tangye Stuart G. , Wu Jun , Aversa Gregorio , de Vries Jan E. , Lanier Lewis L. , Phillips Joseph H. 
Published: December 2022

AbstractT cell activation represents a balance between positive and negative signals delivered via distinct cell surface molecules. Many cytoplasmic protein tyrosine phosphatases are involved in regulating cellular responses by antagonizing the action of protein tyrosine kinases. CD148 is a receptor-type protein tyrosine phosphatase expressed by all human mononuclear cells. We have investigated the effect of CD148 on TCR-mediated activation of human T cells. Overexpression of wild-type, but not a phosphatase-deficient, CD148 in Jurkat T cells inhibited TCR-mediated activation, evidenced by reduced expression of the early activation Ag CD69, inhibition of tyrosine phosphorylation of many intracellular proteins including the critical protein tyrosine kinase ZAP-70, and impairment of mitogen-activated protein kinase activation. Taken together, these results suggest that CD148 is an important phosphatase involved in negatively regulating the proximal signaling events during activation of Ag-specific T cells.
Cutting Edge: IL-4-Independent Induction of Airway Hyperresponsiveness by Th2, But Not Th1, Cells
Authors: Cohn Lauren , Tepper Jeffrey S. , Bottomly Kim 
Published: December 2022

AbstractWe investigated the role of Th1 or Th2 cells in airway hyperresponsiveness (AHR), because both IFN-γ and IL-4 and IL-5-producing CD4 T cells have been identified in the airways of asthmatics. After transfer of in vitro-generated TCR transgenic Th1 or Th2 cells and exposure to inhaled Ag, Th2 cells induced AHR and airway eosinophilia, whereas Th1 cells induced neutrophilic inflammation without AHR. Next, to determine the precise effector function of IL-4 in Th2 cell-induced AHR, we transferred IL-4−/− Th2 cells into wild-type and IL-4−/− recipient mice. After exposure to inhaled Ag, both groups of mice exhibited AHR with markedly reduced airway eosinophilia. Thus, IL-4 production by Th2 cells is not essential for the induction of AHR, but is critical for the migration of eosinophils from lung tissue into the airways.
B Lymphocytes Are Critical Antigen-Presenting Cells for the Initiation of T Cell-Mediated Autoimmune Diabetes in Nonobese Diabetic Mice
Authors: Serreze David V. , Fleming Sara A. , Chapman Harold D. , Richard Scott D. , Leiter Edward H. , Tisch Roland M. 
Published: December 2022

AbstractNonobese diabetic (NOD) mice genetically deficient in B lymphocytes (NOD.Igμnull) are resistant to T cell-mediated autoimmune insulin-dependent diabetes mellitus (IDDM). Ig infusions from diabetic NOD donors did not abrogate IDDM resistance in NOD.Igμnull mice. However, T cell responses to the candidate pancreatic β cell autoantigen glutamic acid decarboxylase (GAD), but not the control Ag keyhole limpet hemocyanin, were eliminated in NOD.Igμnull mice. To initially test whether they contribute to IDDM as APC, NOD B lymphocytes were transferred into NOD.Igμnull recipients. B lymphocytes transferred into unmanipulated NOD.Igμnull recipients were rejected by MHC class I-restricted T cells. Stable T and B lymphocyte repopulation was achieved in irradiated NOD.Igμnull mice reconstituted with syngeneic bone marrow admixed with NOD B lymphocytes. IDDM susceptibility was restored in NOD.Igμnull mice reconstituted with syngeneic marrow plus B lymphocytes, but not with syngeneic marrow only. T cell responses to GAD were restored only in NOD.Igμnull mice reconstituted with syngeneic marrow plus B lymphocytes. Hence, B lymphocytes appear to contribute to IDDM in NOD mice as APC with a preferential ability to present certain β cell Ags such as GAD to autoreactive T cells.
Molecular Mechanisms of Immune-Mediated Lysis of Murine Renal Cancer: Differential Contributions of Perforin-Dependent Versus Fas-Mediated Pathways in Lysis by NK and T Cells
Authors: Sayers Thomas J. , Brooks Alan D. , Lee Jong-Keuk , Fenton Robert G. , Komschlies Kristin L. , Wigginton Jon M. , Winkler-Pickett Robin , Wiltrout Robert H. 
Published: December 2022

AbstractMice bearing the experimental murine renal cancer Renca can be successfully treated with some forms of immunotherapy. In the present study, we have investigated the molecular pathways used by NK and T cells to lyse Renca cells. Renca cells normally express low levels of Fas that can be substantially enhanced by either IFN-γ or TNF-α, and the combination of IFN-γ + TNF-α synergistically enhances cell-surface Fas expression. In addition, cells pretreated with IFN-γ and TNF-α are sensitive to lysis mediated by Fas ligand (FasL)-expressing hybridomas (dllS), cross-linking of anti-Fas Abs or soluble Fas (FasL). Lysis via Fas occurs by apoptosis, since Renca shows all the typical characteristics of apoptosis. No changes in levels of bcl-2 were observed after cytokine treatments. We also examined cell-mediated cytotoxic effects using activated NK cells and T cells from gld FasL-deficient mice, and perforin-deficient mice, as well as wild-type C57BL/6 and BALB/c mice. Interestingly, the granule-mediated pathway predominated in killing of Renca by activated NK cells, while the Fas/FasL pathway contributed significantly to cell-mediated killing of Renca by activated T cells. These results suggest that killing of Renca tumor cells by immune effector cells can occur by both granule and Fas-mediated cytotoxicity. However, for the Fas-mediated pathway to function, cell surface levels of Fas need to be increased beyond a critical threshold level by proinflammatory cytokines such as IFN-γ and TNF-α.
Critical Involvement of Tcf-1 in Expansion of Thymocytes
Authors: Schilham Marco W. , Wilson Anne , Moerer Petra , Benaissa-Trouw Barry J. , Cumano Ana , Clevers Hans C. 
Published: December 2022

Abstract
T cell maturation in Tcf-1−/− mice deteriorates progressively and halts completely around 6 mo of age. During fetal development thymocyte subpopulations seem normal, although total cell numbers are lower. By 4 to 6 wk of age, obvious blockades in the differentiation of CD4−8− thymocytes are observed at two distinct stages (CD44+25+ and CD44−25−), both of which are normally characterized by extensive proliferation. This lack of thymocyte expansion and/or differentiation was also observed when Tcf-1−/− progenitor cells from the aorta-gonad-mesonephros region (embryonic day 11.5), fetal liver (embryonic day 12.5/14.5), and fetal bone marrow (embryonic day 18.5) were allowed to differentiate in normal thymic lobes (fetal thymic organ cultures) or were injected intrathymically into normal recipients. Despite these apparent defects in thymocyte differentiation and expansion, adult Tcf-1−/− mice are immunocompetent, as they generate virus neutralizing Abs at normal titers. Furthermore, their peripheral T cells have an activated phenotype (increased CD44 and decreased CD62L expression) and proliferate normally in response to Ag or mitogen, suggesting that these cells may have arisen from the early wave of development during embryogenesis and are either long lived or have subsequently been maintained by peripheral expansion. As Tcf-1 is a critical component in the Wnt/β-catenin signaling pathway, these data suggest that Wnt-like factors play a role in the expansion of double-negative thymocytes.
Affinity and Kinetic Analysis of the Molecular Interaction of ICAM-1 and Leukocyte Function-Associated Antigen-1
Authors: Tominaga Yuichi , Kita Yasuo , Satoh Atsushi , Asai Satoshi , Kato Kimitoshi , Ishikawa Koichi , Horiuchi Tadashi , Takashi Tohru 
Published: December 2022

AbstractLFA-1 is a member of the β2 integrin family, and interacts with ICAM-1, a member of the Ig superfamily containing five Ig-like domains. Interaction of LFA-1 with ICAM-1 is important in a number of cellular events, including Ag-specific T cell activation and leukocyte transendothelial migration, which are known to be typically transient and highly regulated. In this study, we have used surface plasmon resonance technology to study the ICAM-1/LFA-1 interaction at the molecular level. A soluble form of LFA-1 (sLFA-1), normally expressed as two noncovalently associated membrane-bound subunits, has been produced, and its interaction with ICAM-1 has been examined. The kinetic analysis of a monomeric sLFA-1 binding to the first two domains of ICAM-1 expressed as a chimeric IgG fusion protein (D1D2-IgG) revealed that sLFA-1 was bound to the D1D2-IgG chimera with a Kd of 500 nM and dissociated with a kdiss of 0.1 s−1. Monomeric membrane-bound LFA-1 purified from plasma membranes showed a similar kinetic to sLFA-1. These results suggest that the monovalent interaction between ICAM-1 and LFA-1 has a primarily high affinity and a slow dissociation rate constant as compared with other adhesion molecules, suggesting a potential mechanism for firm adhesion.
Large Protein Fragments as Substrates for Endocytic Antigen Capture by MHC Class II Molecules
Authors: Castellino Flora , Zappacosta Francesca , Coligan John E. , Germain Ronald N. 
Published: December 2022

AbstractAlthough the binding sites of MHC class II molecules can accommodate longer ligands, peptides of 15 to 20 residues are the primary form of processed Ag recovered from class II dimers isolated from living cells. These peptides are derived from intact Ags by proteolysis in endocytic organelles, where binding to class II dimers also occurs. Whether generation of these short peptides typically precedes association with class II molecules, or whether class II molecules initially bind to unfolded proteins or large protein fragments, followed by degradation of the unprotected regions, remains unknown. Here we report the identification of an SDS-stable, long-lived, 120-kDa complex composed of two class II dimers bound to a common large Ag fragment. This complex is produced within the endocytic pathway from newly synthesized MHC class II molecules following exposure of the cells to exogenous hen egg lysozyme. These data suggest that a major pathway of Ag processing involves the initial binding of class II heterodimers to large protein substrates upon exposure of regions with suitable motifs, followed by cleavage and/or trimming of the exposed protein around this bound region. This sequence of events during Ag processing may provide a partial molecular explanation for the immunodominance of certain determinants in protein Ags.
CD3/TCR Complex-Associated Lymphocyte Activation Gene-3 Molecules Inhibit CD3/TCR Signaling
Authors: Hannier Sigrid , Tournier Muriel , Bismuth Georges , Triebel Frédéric 
Published: December 2022

Abstract
The lymphocyte activation gene-3 (LAG-3) molecule is a T cell activation Ag closely related to CD4 at the gene and protein levels. We investigated whether LAG-3 itself may down-regulate the immune response by interfering with TCR signaling. The binding of Ab to the LAG-3 molecule followed by cross-linking (XL) inhibits cell proliferation and cytokine secretion in response to CD3XL on activated T cells. LAG-3XL-induced down-regulation is associated with functional unresponsiveness, as well as with high CD25 expression levels and reversion by exogenous IL-2. It is also associated with a down-modulation of CD3/TCR complex expression. At the biochemical level, LAG-3XL inhibits calcium response to CD3 stimulation. This inhibition is observed with different LAG-3- and CD3-specific mAbs on condition that the two receptors are cross-linked together. Finally, the capping of CD3 was shown to induce cocapping of LAG-3 molecules. Together, these results show that CD3/TCR complex-associated LAG-3 molecules can play an active role in negatively regulating the CD3/TCR activation pathway. They ultimately suggest that LAG-3 is an inhibitory receptor in activated T lymphocytes.
Genomics, Isoforms, Expression, and Phylogeny of the MHC Class I-Related MR1 Gene
Authors: Riegert Patricia , Wanner Valérie , Bahram Seiamak 
Published: December 2022

Abstract
A growing number of non-MHC-encoded class I-related molecules have been shown to perform diverse, yet essential, functions. These include T cell presentation of bacterially derived glycolipidic Ags by CD1, transcytosis of maternal IgG by the neonatal Fc receptor, enriched presence and plausible function within exocrine fluids of the Zn-α2-glycoprotein, subversion of NK cytolytic activity by the CMV UL18 gene product, and, finally, crucial involvement in iron homeostasis of the HFE gene. A recently described member of this family is the MHC class-I related (MR1) gene. The most notable feature of MR1 is undoubtedly its relatively high degree of sequence similarity to the MHC-encoded classical class I genes. The human chromosome 1q25.3 MR1 locus gives rise not only to the originally reported 1,263-bp cDNA clone encoding a putative 341-amino acid polypeptide chain, but to many additional transcripts in various tissues as well. Here we define the molecular identity of all human and murine MR1 isoforms generated through a complex scenario of alternative splicing, some encoding secretory variants lacking the Ig-like α3 domain. Moreover, we show ubiquitous transcription of these MR1 variants in several major cell lineages. We additionally report the complete 18,769-bp genomic structure of the MR1 locus, localize the murine orthologue to a syntenic segment of chromosome 1, and provide evidence for conservation of a single-copy MR1 gene throughout mammalian evolution. The 90% sequence identity between the human and mouse MR1 putative ligand binding domains together with the ubiquitous expression of this gene favor broad immunobiologic relevance.
Production of IgM Hexamers by Normal and Autoimmune B Cells: Implications for the Physiologic Role of Hexameric IgM
Authors: Hughey C. Todd , Brewer Joseph W. , Colosia Ann D. , Rosse Wendell F. , Corley Ronald B. 
Published: December 2022

AbstractSecreted IgM is predominantly found as pentameric molecules, but IgM can also be secreted as hexamers by B cell lines. Murine hexamers activate the complement cascade more efficiently than pentamers, but the physiologic significance of hexameric IgM remains unknown. Here, we report that IgM hexamers and pentamers are cleared from the circulation with similar kinetics, suggesting that the predominance of pentameric IgM in vivo reflects the regulation of polymer assembly and secretion in responding B cells. Normal IgM-secreting B cells, particularly those from the peritoneal cavity, are capable of secreting abundant hexameric IgM in vitro. The disparity between the ability of B cells to secrete IgM hexamers in vitro and the paucity of this polymer in vivo suggest that IgM hexamers might be deleterious. In support of this, we demonstrate that the autoantibodies from a number of patients with cold agglutinin (CA) disease include both IgM hexamers and pentamers. The CA IgM hexamers lyse human erythrocytes in the presence of human complement more efficiently than CA IgM pentamers, suggesting a potential role for hexameric IgM in the pathogenesis of this autoimmune syndrome.