bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Circulating Bovine γδ T Cell Subset, Which Is Found in Large Numbers in the Spleen, Accumulates Inefficiently in an Artificial Site of Inflammation: Correlation with Lack of Expression of E-Selectin Ligands and L-Selectin
Authors: Wilson Eric , Aydintug M. Kemal , Jutila Mark A. 
Published: January 2023

AbstractTissue-specific localization of TCR-defined subsets of γδ T cells has been widely reported; however, the mechanisms responsible for this phenomenon are poorly understood. We describe a bovine γδ T cell TCR-associated subset that preferentially localizes in the spleen. This subset was characterized by coexpression of CD8, and was found to lack surface expression of E-selectin ligands, GR Ag ligands, as well as low expression of L-selectin. The CD8-positive γδ T cell subset did not accumulate at sites of inflammation as efficiently as CD8-negative γδ T cells that, in contrast, express E-selectin and GR ligands and high levels of L-selectin. This is the first demonstration of a γδ T cell subset, which exhibits a defined tissue tropism, having a unique adhesion molecule expression profile. These results demonstrate that in some cases tissue-specific accumulation of γδ T cell subsets can be predicted by expression, or lack of expression, of defined homing molecules.
CTLA4 Signals Are Required to Optimally Induce Allograft Tolerance with Combined Donor-Specific Transfusion and Anti-CD154 Monoclonal Antibody Treatment
Authors: Zheng Xin Xiao , Markees Thomas G. , Hancock Wayne W. , Li Yongsheng , Greiner Dale L. , Li Xian Chan , Mordes John P. , Sayegh Mohammed H. , Rossini Aldo A. , Strom Terry B. 
Published: January 2023

Abstract
Sensitization to donor Ags is an enormous problem in clinical transplantation. In an islet allograft model, presensitization of recipients through donor-specific transfusion (DST) 4 wk before transplantation results in accelerated rejection. We demonstrate that combined DST with anti-CD154 (CD40L) therapy not only prevents the deleterious presensitization produced by pretransplant DST in the islet allograft model, it also induces broad alloantigen-specific tolerance and permits subsequent engraftment of donor islet or cardiac grafts without further treatment. In addition, our data strongly indicate that CTLA4-negative T cell signals are required to achieve prolonged engraftment of skin allograft or tolerance to islet allograft in recipients treated with a combination of pretransplant DST and anti-CD154 mAb. We provide direct evidence that a CD28-independent CTLA4 signal delivers a strong negative signal to CD4+ T cells that can block alloimmune MLR responses. In this study immune deviation into a Th2 (IL-4) response was associated with, but did not insure, graft tolerance, as the inopportune timing of B7 blockade with CTLA4/Ig therapy prevented uniform tolerance but did not prevent Th2-type immune deviation. While CTLA4-negative signals are necessary for tolerance induction, Th1 to Th2 immune deviation cannot be sufficient for tolerance induction. Combined pretransplant DST with anti-CD154 mAb treatment may be attractive for clinical deployment, and strategies aimed to selectively block CD28 without interrupting CTLA4/B7 interaction might prove highly effective in the induction of tolerance.
CD28-Mediated Regulation of mRNA Stability Requires Sequences Within the Coding Region of the IL-2 mRNA
Authors: Ragheb Jack A. , Deen Mary , Schwartz Ronald H. 
Published: January 2023

Abstract
Using sequence-tagged genomic reporter constructs, we investigated the contribution of IL-2 sequences to CD28-mediated regulation of mRNA stability. We find that CD28 signaling acts transiently to stabilize the IL-2 mRNA following T cell activation. Such stabilization requires sequences within both exon 2 and the coding region of exon 4. Unexpectedly, CD28 signaling at later times enhances the decay of the IL-2 mRNA. This CD28-dependent decay of IL-2 mRNA requires sequences localized between exon 3 and the stop codon. Our findings demonstrate that the coding region of the IL-2 mRNA contains previously undefined CD28-responsive sequence elements that are critical for the regulation of mRNA stability.
The Guanine-Nucleotide Exchange Factor Vav Is a Crucial Regulator of B Cell Receptor Activation and B Cell Responses to Nonrepetitive Antigens
Authors: Bachmann Martin F. , Nitschke Lars , Krawczyk Connie , Tedford Kerry , Ohashi Pamela S. , Fischer Klaus D. , Penninger Josef M. 
Published: January 2023

Abstract
The proto-oncogene product Vav is required for receptor clustering, proliferation, and differentiation of T cells, and Vav was identified as a substrate in the TCR and B cell receptor signaling pathway. The role of Vav in B cell responses to Ag challenge in vivo is not known. In this study, we show that Vav regulates B cell proliferation following in vitro activation of Ag receptors, but Vav has no apparent role in CD40-, IL-4-, or LPS-induced B cell activation. Increased degrees of Ag receptor cross-linking can partially reverse the proliferative defect in the anti-IgM response of vav−/− B cells. In vivo, vav−/− mice mounted protective antiviral IgM and IgG responses to infections with vesicular stomatitis virus and recombinant vaccinia virus expressing the vesicular stomatitis virus glycoprotein, which harbor repetitive surface epitopes that directly cross-link the Ag receptor and activate B cells in the absence of T cell help. vav−/− B cells also responded normally to the polyvalent, repetitive hapten Ag trinitrophenyl (TNP)-Ficoll that effectively cross-links B cell receptors. However, vav−/− mice failed to mount immune responses to the nonrepetitive, T cell-dependent hapten Ag (4-hydroxy-5-iodo-3-nitrophenyl)acetyl (NIP)-OVA. These results provide the first genetic evidence on the role of the guanine exchange factor Vav in immune responses to viral infections and antigenic challenge in vivo, and suggest that Vav adjusts the threshold for Ag receptor-mediated B cell activation depending on the nature of the Ag.
Bioactive IL-18 Expression Is Up-Regulated in Crohn’s Disease
Authors: Monteleone Giovanni , Trapasso Francesco , Parrello Tiziana , Biancone Livia , Stella Antonella , Iuliano Rodolfo , Luzza Francesco , Fusco Alfredo , Pallone Francesco 
Published: January 2023

Abstract
An imbalance of immunoregulatory factors is believed to contribute to uncontrolled mucosal Th1 cell activation in Crohn’s disease (CD). IL-18, a macrophage-like cell-derived cytokine, is involved in Th1 clone development, and IFN-γ production. Therefore, IL-18 expression was investigated in CD. Whole mucosal intestinal tissue and lamina propria mononuclear cells (LPMC) of 12 CD and 9 ulcerative colitis (UC) patients and 15 non-inflammatory bowel disease (IBD) controls were tested for IL-18 by semiquantitative RT-PCR and Western blot analysis. Transcripts for IL-18 were found in all samples tested. However, increased IL-18 mRNA accumulation was detected in both mucosal and LPMC samples from CD in comparison to UC and controls. In CD, transcripts for IL-18 were more abundant in the mucosal samples taken from involved areas. An 18-kDa band consistent with mature IL-18 was predominantly found in CD mucosal samples. In mucosal samples from non-IBD controls, IL-18 was present as a 24-kDa polypeptide. Consistently, active IL-1β-converting enzyme (ICE) subunit (p20) was expressed in samples from either CD or UC, whereas, in colonic mucosa from non-IBD controls, ICE was synthesized as precursor (p45) only. To confirm that IL-18 produced in CD tissue was functionally active, CD LPMC were treated with a specific IL-18 antisense oligonucleotide. In these cultures, IL-18 down-regulation was accompanied by a decrease in IFN-γ expression. In aggregate, our data indicate that IL-18 up-regulation is a feature of CD and suggest that IL-18 may contribute to the local immunoinflammatory response in CD.
Humoral Response Suppression Observed with CD23 Transgenics
Authors: Payet Margaret E. , Woodward Elaine C. , Conrad Daniel H. 
Published: January 2023

Abstract
CD23, also known as the low affinity IgE receptor (FcεRII), has been hypothesized to have a role in IgE regulation. A new CD23 transgenic mouse was generated using the MHC class I promoter and IgH enhancer to further test the hypothesis that CD23 plays a role in the down-regulation of IgE. Study of three founder lines by FACS showed overexpression to varying extents on both B and T lymphocytes. No alterations in lymphocyte populations was observed. All three founder lines exhibited strong suppression of IgE in response to DNP-keyhole limpet hemocyanin/alum and Nippostrongylus brasiliensis infection compared with that in parental or littermate controls. The founder line exhibiting the highest level of suppression also was less susceptible to Ag-induced systemic anaphylactic shock. Overall, the data support the concept that enhancing CD23 levels can be used to suppress IgE-mediated disease. The mechanism involves decreased IgE synthesis, because the serum half-life of IgE was not altered in transgenics, and enzyme-linked immunospot analysis demonstrated lower IgE-producing cells stimulated by injection of anti-IgD. Transgenics also exhibited significantly decreased IgG1 responses and exhibited lower levels of all Ig isotypes, although this was more variable in different founder lines.
BALB/c Invariant Chain Mutant Mice Display Relatively Efficient Maturation of CD4+ T Cells in the Periphery and Secondary Proliferative Responses Elicited upon Peptide Challenge
Authors: Kenty George , Bikoff Elizabeth K. 
Published: January 2023

AbstractAllelic differences are known to influence many important aspects of class II biosynthesis, including subunit assembly, Ii chain associations, and DM-mediated peptide loading. Mutant mouse strains lacking Ii chain expression have been previously studied on mixed genetic backgrounds. The present experiments describe cellular and functional characteristics of congenic BALB/c Ii chain mutants. As expected, class II surface expression was markedly decreased, but in contrast to I-Ad-transfected cell lines, serological analysis of BALB/c Ii chain-deficient spleen cells gave no evidence for discordant expression of class II conformational epitopes. Thus, we conclude that properly folded class II molecules are exported via the Ii chain-independent pathway. Functional assays demonstrate consistently superior peptide-loading capabilities, suggesting that these I-Ad molecules are empty or occupied by an easily displaced peptide(s). Defective B cell development was observed for three mutant strains established on diverse genetic backgrounds. Ii chain function is also essential for optimal class II surface expression by mature splenic dendritic cells. Surprisingly, we observe in BALB/c Ii chain mutants, relatively efficient maturation of CD4+ T cells in the periphery and secondary proliferative responses elicited upon peptide challenge. The milder phenotype displayed by BALB/c Ii chain mutants in comparison with class II functional defects previously described for mouse strains lacking Ii chain is likely to have an effect on disease susceptibility.
Enhancer-Blocking Activity Within the DNase I Hypersensitive Site 2 to 6 Region Between the TCR α and Dad1 Genes
Authors: Zhong Xiao-Ping , Krangel Michael S. 
Published: January 2023

AbstractAlthough tightly linked, the TCR α and δ genes are expressed specifically in T lymphocytes, whereas the Dad1 gene is ubiquitously expressed. Between TCR α and Dad1 are eight DNase I hypersensitive sites (HS). HS1 colocalizes with the TCR α enhancer (Eα) and is T cell-specific; HS2, -3, -4, -5, and -6 map downstream of HS1 and are tissue-nonspecific. The region spanning HS2–6 was reported to display chromatin-opening activity and to confer copy number-dependent and integration site-independent transgene expression in transgenic mice. Here, we demonstrate that HS2–6 also displays enhancer-blocking activity, as it can block an enhancer from activating a promoter when located between the two in a chromatin-integrated context, and can do so without repressing either the enhancer or the promoter. Multiple enhancer-blocking elements are arrayed across HS2–6. We show that HS2–6 by itself does not activate transcription in chromatin context, but can synergize with an enhancer when located upstream of an enhancer and promoter. We propose that HS2–6 primarily functions as an insulator or boundary element that may be critical for the autonomous regulation of the TCR α and Dad1 genes.
Presentation of the Self Antigen Myelin Basic Protein by Dendritic Cells Leads to Experimental Autoimmune Encephalomyelitis
Authors: Dittel Bonnie N. , Visintin Irene , Merchant Raina M. , Janeway Charles A. 
Published: January 2023

AbstractBone marrow (BM)-derived dendritic cells (DC) are potent stimulators of naive CD4+ T cell activation. Because DC are efficient at Ag processing and could potentially present self Ags, we investigated the role of DC in the presentation of an encephalitogenic peptide from myelin basic protein (Ac1–11) in the induction of experimental autoimmune encephalomyelitis (EAE). To determine if DC could prime for EAE, we transferred DC pulsed with Ac1–11 or with medium alone into irradiated mice in combination with CD4+ T cells isolated from a mouse transgenic for a TCR specific for Ac1–11 + I-Au. Mice transferred with Ac1–11-pulsed DC developed EAE 7–10 days later, whereas mice receiving medium-pulsed DC did not. By day 15, all mice given peptide-loaded DC had signs of tail and hind limb paralysis, and by day 20 infiltration of Ac1–11-specific CD4+ T cells was detected in the brain parenchyma. We also demonstrated interactions between Ac1–11-pulsed DC and Ac1–11-specific T cells in the lymph nodes 24 h following adoptive transfer of both cell populations. These data show that DC can efficiently present the self Ag myelin basic protein Ac1–11 to Ag-specific T cells in the periphery of mice to induce EAE.
A Non-AUG-Defined Alternative Open Reading Frame of the Intestinal Carboxyl Esterase mRNA Generates an Epitope Recognized by Renal Cell Carcinoma-Reactive Tumor-Infiltrating Lymphocytes In Situ
Authors: Ronsin Christophe , Chung-Scott Véronique , Poullion Isabelle , Aknouche Nicolas , Gaudin Catherine , Triebel Frédéric 
Published: January 2023

Abstract
A number of Ags recognized by tumor-reactive T cells have been characterized, including nonmutated gene products and a variety of epitopes shown to arise from either mutated or alternatively processed transcripts. Here, we report that the screening of a cDNA library with an HLA-B7-restricted renal cell carcinoma-reactive T cell clone derived from tumor-infiltrating lymphocytes (TILs) that were clonally amplified in vivo (as assessed by TCRBV complementarity determining region-3 length distribution analysis) resulted in the isolation of a nonamer encoded by an alternative open reading frame (ORF) (a +1 frameshift) of the intestinal carboxyl esterase gene. This peptide binds HLA-B*0702-presenting molecules as assessed in an immunofluorescence-based peptide binding assay using transfected T2 cells. Constitutive expression of this alternative ORF protein was observed in all transformed HLA-B7+ renal cell lines that were recognized in cytotoxicity assays by the TILs. The intestinal carboxyl esterase gene is transcribed in renal cell carcinoma tumors as well as in normal liver, intestinal, or renal tissues. Mutation of the natural ATG translation initiation site did not alter recognition, indicating that frameshifting (i.e., slippage of the ribosome forward) and recoding are not involved. In addition, a point mutation of the three AUG codons that may be used as alternative translation initiation sites in the +1 ORF did not abolish recognition, whereas mutation of an upstream ACG codon did, indicating that the latter codon initiates the translation of the alternative ORF. These results further extend the types of Ags that can be recognized by tumor-reactive TILs in situ (i.e., leading to clonal T cell expansion).
Efficient Transfer of a Tumor Antigen-Reactive TCR to Human Peripheral Blood Lymphocytes Confers Anti-Tumor Reactivity
Authors: Clay Timothy M. , Custer Mary C. , Sachs Jessica , Hwu Patrick , Rosenberg Steven A. , Nishimura Michael I. 
Published: January 2023

Abstract
The tumor-associated-Ag MART-1 is expressed by most human melanomas. The genes encoding an αβ TCR from a MART-1-specific, HLA-A2-restricted, human T cell clone have been efficiently transferred and expressed in human PBL. These retrovirally transduced PBL cultures were MART-1 peptide reactive, and most cultures recognized HLA-A2+ melanoma lines. Limiting dilution clones were generated from three bulk transduced PBL cultures to investigate the function of individual clones within the transduced cultures. Twenty-nine of 29 CD8+ clones specifically secreted IFN-γ in response to T2 cells pulsed with MART-1(27–35) peptide, and 23 of 29 specifically secreted IFN-γ in response to HLA-A2+ melanoma lines. Additionally, 23 of 29 CD8+ clones lysed T2 cells pulsed with the MART-1(27–35) peptide and 15 of 29 lysed the HLA-A2+ melanoma line 888. CD4+ clones specifically secreted IFN-γ in response to T2 cells pulsed with the MART-1(27–35) peptide. TCR gene transfer to patient PBL can produce CTL with anti-tumor reactivity in vitro and could potentially offer a treatment for patients with metastatic melanoma. This approach could also be applied to the treatment of other tumors and viral infections. Additionally, TCR gene transfer offers unique opportunities to study the fate of adoptively transferred T cells in vivo.
Cutting Edge: Trimolecular Interaction of TCR with MHC Class II and Bacterial Superantigen Shows a Similar Affinity to MHC:Peptide Ligands
Authors: Redpath Stella , Alam S. Munir , Lin Christina M. , O’Rourke Anne M. , Gascoigne Nicholas R. J. 
Published: January 2023

Abstract
Bacterial superantigens such as Staphylococcus aureus enterotoxin A (SEA) are very potent stimulators of T cells. They bind to the Vβ region of the TCR and to MHC class II, stimulating T cells at nanomolar concentrations. Using surface plasmon resonance measurements, we find that binding between the individual components of the complex (TCR-class II, TCR-SEA, SEA-class II) is very weak, but that the stability of the trimolecular complex is considerably enhanced, reaching an affinity similar to that found for TCR interactions with MHC:peptide ligand. Thus, the potency of SEA in stimulation of T cells is not due to particularly strong affinities between the proteins, but to a cooperative effect of interactions in the TCR-SEA-MHC class II trimolecular complex that brings the kinetics into a similar range to binding of conventional Ags. This range may be the optimum for T cell activation.
Role of Inflammatory Infiltrate in Activation and Effector Function of Cloned Islet Reactive Nonobese Diabetic CD8+ T Cells: Involvement of a Nitric Oxide-Dependent Pathway
Authors: Gurlo Tatyana , Kawamura Kenneth , von Grafenstein Hermann 
Published: January 2023

Abstract
To investigate how CD8+ T cells interact with β cells and local inflammatory cells in islets, we have isolated CD8+ T cell clones from nonobese diabetic (NOD) spleen that recognize and destroy both islets and the NOD insulinoma cell line NIT-1. The clones destroyed NOD islets with pre-existing inflammation better than islets without signs of inflammation. Islets from NOD-scid mice were destroyed only poorly, but that could be improved by adding IL-7 to the assay. Anti-IFN-γ Abs inhibited destruction of infiltrated islets. Single islets were effective stimulators of IFN-γ production by cloned CD8+ T cells, which varied &gt;50-fold depending on the degree of islet infiltration. This effect of the islet mononuclear infiltrate could be mimicked by adding spleen cells to NIT-1 cells, which augmented IFN-γ production above the level stimulated by NIT-1 cells alone. The enhancing effect of spleen cells could be attributed to their macrophage subpopulation and was not MHC restricted, although recognition of islet Ag by cloned CD8+ T cells and subsequent islet destruction was restricted to islets expressing H-2Db molecules. An inhibitor of inducible NO synthase inhibited destruction of inflamed islets by cloned CD8+ T cells. We propose that macrophages in inflamed islets provide a form of bystander costimulation of β cell-specific CD8+ T cells. CD8+ T cells respond to Ag and costimulation by producing IFN-γ that activates macrophages. Activated macrophages facilitate islet destruction by CD8+ T cells through a NO synthesis-dependent pathway.
IL-5 and Rp105 Signaling Defects in B Cells from Commonly Used 129 Mouse Substrains
Authors: Corcoran Lynn M. , Metcalf Donald 
Published: January 2023

AbstractThe use of 129 strain-derived embryonic stem cell lines for targeted gene mutation in mice has led directly to an expanded use of this inbred strain worldwide. It has been noted, however, that the 129 genetic background can make a significant contribution to the severity of a mutant phenotype. In this study, we reveal a specific defect in the IL-5 and Rp105 responses of B lymphocytes from two widely used 129 mouse substrains. The response to stimulation through surface IgM is also diminished, although to a lesser degree, in these mice. The lesion appears to reduce significantly the expression of the α-chain of the IL-5R, but may also influence events downstream of the IL-5R. This phenotype displays a codominant inheritance pattern, and is accompanied by a variable but significant depression of peritoneal B-1 cell numbers in 50% of the mice.
Molecular and Functional Characterization of Mouse Signaling Lymphocytic Activation Molecule (SLAM): Differential Expression and Responsiveness in Th1 and Th2 Cells
Authors: Castro Antonio G. , Hauser Thomas M. , Cocks Benjamin G. , Abrams John , Zurawski Sandra , Churakova Tatyana , Zonin Francesca , Robinson Douglas , Tangye Stuart G. , Aversa Gregorio , Nichols Kim E. , de Vries Jan E. , Lanier Lewis L. , O’Garra Anne 
Published: January 2023

AbstractOptimal T cell activation and expansion require engagement of the TCR plus costimulatory signals delivered through accessory molecules. SLAM (signaling lymphocytic activation molecule), a 70-kDa costimulatory molecule belonging to the Ig superfamily, was defined as a human cell surface molecule that mediated CD28-independent proliferation of human T cells and IFN-γ production by human Th1 and Th2 clones. In this study, we describe the cloning of mouse SLAM and the production of mAb against it which reveal its expression on primary mouse T and B cells. Mouse SLAM is expressed on highly polarized Th1 and Th2 populations, and is maintained on Th1, but not on Th2 clones. Anti-mouse SLAM mAb augmented IFN-γ production by Th1 cells and Th1 clones stimulated through the TCR, but did not induce IFN-γ production by Th2 cells, nor their production of IL-4 or their proliferation. Mouse SLAM is a 75-kDa glycoprotein that upon tyrosine phosphorylation associates with the src homology 2-domain-containing protein tyrosine phosphatase SHP-2, but not SHP-1. Mouse SLAM also associates with the recently described human SLAM-associated protein. These studies may provide new insights into the regulation of Th1 responses.1 DNAX is supported by the Schering Plough Research Institute. T.M.H. was initially funded by fellowships from the Swiss National Science Foundation and from the Roche Research Foundation, Switzerland.      Abbreviations used in this paper: SLAM, signaling lymphocytic activation molecule; AP, alkaline phosphatase; h, human; m, mouse; SAP, SLAM-associated protein; SH2, Src homology 2; SHP, SH2 domain-bearing protein tyrosine phosphatase; XLP, X-linked lymphoproliferative disease; PIG, phosphatidylinositol glycan.