bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cutting Edge: CD40 Ligand Is a Limiting Factor in the Humoral Response to T Cell-Dependent Antigens
Authors: Pérez-Melgosa Mercedes , Hollenbaugh Diane , Wilson Christopher B. 
Published: December 2022

AbstractCD40 ligand (CD40L) plays a crucial role in T cell-dependent B cell responses, but whether its abundance is a limiting factor in their development is unclear. This question was addressed in transgenic mice expressing the murine CD40L gene under the control of the IL-2-promoter (CD40Ltg+). The fraction of activated T cells from the CD40Ltg+ mice with detectable levels of surface CD40L was modestly greater (1.1- to 2-fold) than littermate controls and paralleled an ∼1.8-fold increase in CD40L mRNA abundance. In response to trinitrophenol (TNP)-keyhole limpet hemocyanin and tetanus/diphtheria vaccine, CD40Ltg+ mice developed higher titers of high-affinity IgG and IgG1 Ab than wild-type mice. In contrast, the Ab response of CD40Ltg+ and control mice was similar in response to the T-independent Ag TNP-Ficoll. These results suggest that a modest increment in expression of CD40L accelerates the development of T-dependent responses, and that CD40L plays a limiting role in the induction of high-affinity Ab and Ab-class switching.
Cutting Edge: Lymphoproliferative Disease in the Absence of CTLA-4 Is Not T Cell Autonomous
Authors: Bachmann Martin F. , Köhler Gabriele , Ecabert Barbara , Mak Tak W. , Kopf Manfred 
Published: December 2022

AbstractMice deficient for the expression of CTLA-4 develop a lethal lymphoproliferative syndrome and multiorgan inflammation leading to death at about 4 wk of age. Here we show that RAG2-deficient mice reconstituted with CTLA-4-deficient bone marrow do not develop a lymphoproliferative syndrome despite lymphocyte infiltration mainly into pericardium and liver. Moreover, RAG2-deficient mice reconstituted with a mixture of normal and CTLA-4-deficient bone marrow remain healthy and do not develop any disease. Thus, the lethal disease observed in CTLA-4-deficient mice is not T cell autonomous and can be prevented by factors produced by normal T cells.
A Soluble Form of IL-13 Receptor α1 Promotes IgG2a and IgG2b Production by Murine Germinal Center B Cells
Authors: Poudrier Johanne , Graber Pierre , Herren Suzanne , Gretener Denise , Elson Greg , Berney Claude , Gauchat Jean-François , Kosco-Vilbois Marie H. 
Published: December 2022

AbstractA functional IL-13R involves at least two cell surface proteins, the IL-13Rα1 and IL-4Rα. Using a soluble form of the murine IL-13Rα1 (sIL-13R), we reveal several novel features of this system. The sIL-13R promotes proliferation and augmentation of Ag-specific IgM, IgG2a, and IgG2b production by murine germinal center (GC) B cells in vitro. These effects were enhanced by CD40 signaling and were not inhibited by an anti-IL4Rα mAb, a result suggesting other ligands. In GC cell cultures, sIL-13R also promoted IL-6 production, and interestingly, sIL-13R-induced IgG2a and IgG2b augmentation was absent in GC cells isolated from IL-6-deficient mice. Furthermore, the effects of the sIL-13R molecule were inhibited in the presence of an anti-IL-13 mAb, and preincubation of GC cells with IL-13 enhanced the sIL-13R-mediated effects. When sIL-13R was injected into mice, it served as an adjuvant-promoting production to varying degrees of IgM and IgG isotypes. We thus propose that IL-13Rα1 is a molecule involved in B cell differentiation, using a mechanism that may involve regulation of IL-6-responsive elements. Taken together, our data reveal previously unknown activities as well as suggest that the ligand for the sIL-13R might be a component of the IL-13R complex or a counterstructure yet to be defined.
Induction of Glutamic Acid Decarboxylase 65-Specific Th2 Cells and Suppression of Autoimmune Diabetes at Late Stages of Disease Is Epitope Dependent
Authors: Tisch Roland , Wang Bo , Serreze David V. 
Published: December 2022

Abstract
Peptide-based immunotherapy is one strategy by which to selectively suppress the T cell-mediated destruction of β cells and treat insulin-dependent diabetes mellitus (IDDM). Here, we investigated whether a panel of T cell epitopes derived from the β cell autoantigen glutamic acid decarboxylase 65 (GAD65) differ in their capacity to induce Th2 cell function in nonobese diabetic (NOD) mice and in turn prevent overt IDDM at different preclinical stages of disease development. The panel consists of GAD65-specific peptides spanning aa 217–236 (p217), 247–265 (p247), 290–309 (p290), and 524–543 (p524). Our studies revealed that all of the peptides effectively prevented insulitis and diabetes when administered to NOD mice before the onset of insulitis. In contrast, only a mixture of p217 and p290 prevented progression of insulitis and overt IDDM in NOD mice exhibiting extensive β cell autoimmunity. Immunization with the GAD65-specific peptides did not block IDDM development in NOD mice deficient in IL-4 expression. These findings demonstrate that GAD65-specific peptide immunotherapy effectively suppresses progression to overt IDDM, requires the production of IL-4, and is dependent on the epitope targeted and the extent of preexisting β cell autoimmunity in the recipient.
CpG Oligodeoxynucleotides Down-Regulate Macrophage Class II MHC Antigen Processing
Authors: Chu Rose S. , Askew David , Noss Erika H. , Tobian Aaron , Krieg Arthur M. , Harding Clifford V. 
Published: December 2022

AbstractUnmethylated CpG motifs in bacterial DNA or short oligodeoxynucleotides (ODN) stimulate cells of the immune system and provide adjuvant activity. CpG DNA directly activates macrophages to secrete IL-12 and TNF-α and increases transcription of various genes, but its effects on macrophage Ag processing remain uncertain. The effects of CpG ODN on class II MHC (MHC-II) Ag processing and presentation were examined using peritoneal macrophages that were cultured for 18 h with CpG ODN and then pulsed with protein Ags. T cell hybridomas were used to detect presentation of specific peptide:MHC-II complexes. Both CpG ODN and LPS inhibited processing of bovine RNase and hen egg lysozyme. Presentation of exogenous peptides was inhibited to a lesser degree. Treatment of macrophages for 18 h with CpG ODN decreased surface MHC-II expression, as measured by flow cytometry. Furthermore, Northern blot analysis revealed that treatment with CpG ODN decreased I-Ak mRNA. Endocytosis by macrophages, as measured by uptake of fluorescent dextran, was not altered by treatment with CpG ODN. The inhibitory effect of CpG ODN on Ag processing was seen after prolonged (18 h) treatment of macrophages, but not after short treatment (e.g., 2 h) with CpG ODN and protein Ag. Enhancement of macrophage Ag processing was not seen at any time point of CpG ODN exposure, in contrast to data from other studies with dendritic cells. In summary, exposure of macrophages to CpG ODN results in a decrease in macrophage Ag processing and presentation, which is largely mediated by a decrease in synthesis of MHC-II molecules.
Fas Is Expressed Early in Human Thymocyte Development But Does Not Transmit an Apoptotic Signal
Authors: Jenkins Morgan , Keir Mary , McCune Joseph M. 
Published: December 2022

AbstractWe investigated the expression and function of Fas on human thymocytes prepared from fetal and pediatric tissue specimens and from SCID-hu Thy/Liv grafts. Unlike mouse thymocytes, human thymocytes exhibited a pattern of Fas expression skewed to immature cells, in that the highest expression was seen on double negative thymocytes and on intrathymic T progenitor cells. Fas expression was intermediate on double positive human thymocytes, and low or negative on mature single positive CD4 and CD8 medullary thymocytes. In spite of this relatively abundant surface expression, cross-linking of Fas with agonist mAb was incapable of triggering an apoptotic signal in human thymocytes. Apoptotic signaling was not enhanced by treatment with cycloheximide, nor by restoring a cosignaling milieu by addition of thymic stromal cells. Mouse thymocytes were induced to apoptosis by cross-linked recombinant soluble human Fas ligand both in vitro and in vivo, though human thymocytes were also resistant to this mode of receptor ligation. Membrane-bound Fas ligand also induced apoptotic death in murine thymocytes but not in human thymocytes. Human thymocytes were as sensitive as Jurkat cells, however, to apoptosis induced by TNF-α, suggesting that these cells have a signaling defect before activation of the earliest caspases. These data demonstrate a durable and specific resistance of human thymocytes to apoptosis induced through Fas receptor engagement, and reveal significant species-specific differences in the biology of thymocyte-programmed cell death.
Expression of L-Selectin on Th1 Cells Is Regulated by IL-12
Authors: Wely Cathy A. van , Beverley Peter C. L. , Brett Sara J. , Britten Christopher J. , Tite John P. 
Published: December 2022

AbstractL-selectin has become established as a key molecule in the recirculation of naïve T cells from the blood to peripheral lymph nodes, yet little is known about its role in the migration of effector or memory cells. While differentiating naïve CD4+ T cells into Th1 and Th2 subsets in vitro, it was noted that L-selectin levels were maintained on the Th1 subset of cells. The expression of L-selectin on the Th1 cells appeared to be dependent on the presence of IL-12. Th2 cells, differentiated in the absence of IL-12, failed to maintain L-selectin expression. Coculture with IL-12, IL-18, IL-4, TNF-α, or IFN-α, -β, or -γ demonstrated a dependence on IL-12 alone for L-selectin expression. In addition, the inclusion of heat-killed Listeria monocytogenes in the cultures also maintained L-selectin expression on the Th1 cells. In all cultures, the maintenance of L-selectin on the T cell surface could be blocked by the inclusion of anti-IL-12 Abs. Analysis of the mRNA levels for L-selectin in T cells, differentiated in the presence or absence of IL-12, showed that the cytokine appears to exert its effect on L-selectin at the transcriptional level. Given the key role played by IL-12 in the differentiation of naïve T cells into the Th1 subset, the observation that IL-12 can also regulate L-selectin expression has implications for the migration of Th1 effector cells both through the lymphatic system and to sites of inflammation.
On the Lifespan of Virgin T Lymphocytes
Authors: Di Rosa Francesca , Ramaswamy Sridhar , Ridge John P. , Matzinger Polly 
Published: December 2022

AbstractTo study the lifespan of virgin T lymphocytes, we removed the thymus from adult female mice and then, at various times afterward, tested their ability to mount an immune response to a newly encountered Ag, the male Ag H-Y. We found that unprimed thymectomized mice were able to generate a primary response to H-Y for some time after thymectomy but lost this ability at ∼6 mo. In contrast, mice that were primed to H-Y just after thymectomy continued to display immunological memory to H-Y for &gt;1 year. These experiments show that primary immune responses disappear in the absence of a thymus.
Synergistic Action of fms-Like Tyrosine Kinase 3 Ligand and CD40 Ligand in the Induction of Dendritic Cells and Generation of Antitumor Immunity In Vivo
Authors: Borges Luis , Miller Robert E. , Jones Jon , Ariail Kiley , Whitmore James , Fanslow William , Lynch David H. 
Published: December 2022

AbstractDaily treatment of mice with fms-like tyrosine kinase 3 ligand (Flt3L) leads to a significant increase in the number of dendritic cells and induces antitumor immunity. Here, we show that Flt3L and CD40 ligand (CD40L) synergize in the generation of immune responses against two poorly immunogenic tumors, leading to complete tumor rejection in a high proportion of mice. Rechallenge of the Flt3L + CD40L-treated mice with the immunizing tumor resulted in complete inhibition of tumor growth, indicating that these animals had developed long-lasting antitumor immunity. In addition, we demonstrate that endogenous CD40L plays a critical role in antitumor immunity, since blockade of CD40-CD40L interactions in vivo prevents the generation of antitumor immunity in therapeutic and vaccination protocols. Dendritic cells generated in mice treated with Flt3L alone or in combination with CD40L were equally potent in stimulating allogeneic T cells and expressed similar levels of MHC class II, CD80, and CD86. However, mice treated with Flt3L + CD40L had significantly more dendritic cells than mice treated with either of the cytokines alone, suggesting that CD40L promotes the proliferation and/or survival of dendritic cells generated by Flt3L treatment. Dendritic cells generated in this manner are likely to be involved in the priming of antitumor immune responses.
Primed T Cells Are More Resistant to Fas-Mediated Activation-Induced Cell Death than Naive T Cells
Authors: Inaba Motoko , Kurasawa Kazuhiro , Mamura Mizuko , Kumano Kotaro , Saito Yasushi , Iwamoto Itsuo 
Published: December 2022

AbstractMemory T cells respond in several functionally different ways from naive T cells and thus function as efficient effector cells. In this study we showed that primed T cells were more resistant to Fas-mediated activation-induced cell death (AICD) than naive T cells using OVA-specific TCR transgenic DO10 mice and Fas-deficient DO10 lpr/lpr mice. We found that apoptosis was efficiently induced in activated naive T cells at 48 and 72 h after Ag restimulation (OVA peptide; 0.3 and 3 μM), whereas apoptosis was not significantly increased in activated primed T cells at 24–72 h after Ag restimulation. We further showed that the resistance to AICD in primed T cells was due to the decreased sensitivity to apoptosis induced by Fas-mediated signals, but TCR-mediated signaling equally activated both naive and primed T cells to induce Fas and Fas ligand expressions. Furthermore, we demonstrated that primed T cells expressed higher levels of Fas-associated death domain-like IL-1β-converting enzyme inhibitory protein (FLIP), an inhibitor of Fas-mediated apoptosis, at 24–48 h after Ag restimulation than naive T cells. In addition, Bcl-2 expression was equally observed between activated naive and primed T cells after Ag restimulation. Thus, these results indicate that naive T cells are sensitive to Fas-mediated AICD and are easily deleted by Ag restimulation, while primed/memory T cells express higher levels of FLIP after Ag restimulation, are resistant to Fas-mediated AICD, and thus function as efficient effector cells for a longer period.
Thymus-Derived Glucocorticoids Set the Thresholds for Thymocyte Selection by Inhibiting TCR-Mediated Thymocyte Activation
Authors: Vacchio Melanie S. , Lee Jan Y. M. , Ashwell Jonathan D. 
Published: December 2022

AbstractSelection processes in the thymus eliminate nonfunctional or harmful T cells and allow the survival of those cells with the potential to recognize Ag in association with self-MHC-encoded molecules (Ag/MHC). We have previously demonstrated that thymus-derived glucocorticoids antagonize TCR-mediated deletion, suggesting a role for endogenous thymic glucocorticoids in promoting survival of thymocytes following TCR engagement. Consistent with this hypothesis, we now show that inhibition of thymus glucocorticoid biosynthesis causes an increase in thymocyte apoptosis and a decrease in recovery that are directly proportional to the number of MHC-encoded molecules present and, therefore, the number of ligands available for TCR recognition. Expression of CD5 on CD4+CD8+ thymocytes, an indicator of TCR-mediated activation, increased in a TCR- and MHC-dependent manner when corticosteroid production or responsiveness was decreased. These results indicate that thymus-derived glucocorticoids determine where the window of thymocyte selection occurs in the TCR avidity spectrum by dampening the biological consequences of TCR occupancy and reveal that glucocorticoids mask the high percentage of self-Ag/MHC-reactive thymocytes that exist in the preselection repertoire.
On the Role of Feedback in Promoting Conflicting Goals of the Adaptive Immune System
Authors: Segel Lee A. , Bar-Or Ruth Lev 
Published: December 2022

Abstract
We explored here the implications of two premises. 1) In their response over days or weeks to pathogen invasion, cells of the immune system combine several overlapping and perhaps contradictory goals. 2) The immune system has ways to monitor progress toward these goals via receptors that bind chemicals whose concentrations are related to such progress. We illustrate with simple mathematical models how such monitoring can lead to feedbacks that improve the efficiency of a given effector type in accomplishing its specialized task, and also how feedbacks can shift the balance among a variety of effectors toward a preponderance of the more effective. Specific suggestions are given for feedback molecules.
Human Blood Dendritic Cell-Like B Cells Isolated by the 5G9 Monoclonal Antibody Reactive with a Novel 220-kDa Antigen
Authors: Zhong Rui-Kun , Donnenberg Albert D. , Zhang Hai-Fan , Watkins Simon , Zhou Jie-Hua , Ball Edward D. 
Published: December 2022

AbstractWe developed a murine IgG1 mAb, 5G9, following immunization of a BALB/c mouse with Daudi cells. By immunoprecipitation, 5G9 reacted with a 220-kDa Ag on Daudi cells, which reduced to four subunits (55, 65, 80, and 85 kDa). mAb 5G9 bound to 40–60% of peripheral blood B cells, weakly reacted with monocytes and granulocytes, and did not bind to erythrocytes, platelets, T cells, or NK cells. mAb 5G9 brightly stained scattered cells in human tonsil sections, which appeared to be dendritic cells (DC) by morphology. mAb 5G9 also stained scattered cells in cytospin slides of monocyte-derived DC with long, thin, beaded membrane processes, morphologically distinct from other monocyte-derived DC. Positive selection of blood mononuclear cells with mAb 5G9 and sheep anti-mouse IgG Dynabeads demonstrated an enriched population of DC. By flow cytometry analysis, these cells were CD19, CD20, CD22, CD40, CD44, CD83, CD86, IgD, and HLA-Dr positive and either κ- or λ-L chain positive. They did not express CD3, CD4, CD5, CD10, CD11b, CD13, CD25, CD56, CD14, CD33, or CD64. Isolated 5G9+ cells were potent APCs in allogeneic MLR, compared with 5G9− PBMC, 5G9− B cells, monocytes, and monocytes cultured in IL-4 and GM-CSF for 24 h. mAb 5G9 defines a novel peripheral blood cell with B cell phenotype and DC morphology and function: DC-like B cells. The significance of this cell in immune responses requires further study.
A CD1a+/CD11c+ Subset of Human Blood Dendritic Cells Is a Direct Precursor of Langerhans Cells
Authors: Ito Tomoki , Inaba Muneo , Inaba Kayo , Toki Junko , Sogo Shinji , Iguchi Tomoko , Adachi Yasushi , Yamaguchi Kazuyuki , Amakawa Ryuichi , Valladeau Jenny , Saeland Sem , Fukuhara Shirou , Ikehara Susumu 
Published: December 2022

AbstractBased on the relative expression of CD11c and CD1a, we have identified three fractions of dendritic cells (DCs) in human peripheral blood, including a direct precursor of Langerhans cells (LCs). The first two fractions were CD11c+ DCs, comprised of a major CD1a+/CD11c+ population (fraction 1), and a minor CD1a−/CD11c+ component (fraction 2). Both CD11c+ fractions displayed a monocyte-like morphology, endocytosed FITC-dextran, expressed CD45RO and myeloid markers such as CD13 and CD33, and possessed the receptor for GM-CSF. The third fraction was comprised of CD1a−/CD11c− DCs (fraction 3) and resembled plasmacytoid T cells. These did not uptake FITC-dextran, were negative for myeloid markers (CD13/CD33), and expressed CD45RA and a high level of IL-3Rα, but not GM-CSF receptors. After culture with IL-3, fraction 3 acquired the characteristics of mature DCs; however, the expression of CD62L (lymph node-homing molecules) remained unchanged, indicating that fraction 3 can be a precursor pool for previously described plasmacytoid T cells in lymphoid organs. Strikingly, the CD1a+/CD11c+ DCs (fraction 1) quickly acquired LC characteristics when cultured in the presence of GM-CSF + IL-4 + TGF-β1. Thus, E-cadherin, Langerin, and Lag Ag were expressed within 1 day of culture, and typical Birbeck granules were observed. In contrast, neither CD1a−/CD11c+ (fraction 2) nor CD1a−/CD11c− (fraction 3) cells had the capacity to differentiate into LCs. Furthermore, CD14+ monocytes only expressed E-cadherin, but lacked the other LC markers after culture in these cytokines. Therefore, CD1a+/CD11c+ DCs are the direct precursors of LCs in peripheral blood.
IL-10 Transgenic Mice Present a Defect in T Cell Development Reminiscent to SCID Patients
Authors: Rouleau Matthieu , Cottrez Françoise , Bigler Mike , Antonenko Sevtlana , Carballido José M. , Zlotnik Albert , Roncarolo Maria-Grazia , Groux Hervé 
Published: December 2022

AbstractTo analyze the effect of IL-10 overexpressed by APCs as observed in some SCID patients, we have expressed the human IL-10 cDNA under the control of the murine MHC class II promoter in transgenic mice. Similar to SCID patients, these mice presented a defect in T cell maturation characterized by a rapid thymic aplasia that started after birth. The blockage in T cell maturation was strictly restricted to TCR-αβ T cells as the absolute number of thymic dendritic, TCR-γδ and NK1.1 T cells were equivalent to control littermates. Crossing IL-10 transgenic mice with TCR transgenic mice or treatment with staphylococcal enterotoxin B showed that the defect was not related to the impairment of positive or negative selection. However, repopulating of IL-10 transgenic mouse-fetal thymic organ culture with different stages of triple negative T cells isolated from control mice showed that the blockage occurred specifically at the pre-T cell stage and was reverted by treatment with blocking anti-IL-10 mAbs. These results demonstrate that IL-10 regulates T cell maturation and that dysregulation of IL-10 expression can lead to severe T cell immunodeficiency.
A Novel CD8 T Cell-Restricted CD45RB Epitope Shared by CD43 Is Differentially Affected by Glycosylation
Authors: Carlow Douglas A. , Ardman Blair , Ziltener Hermann J. 
Published: December 2022

AbstractThe mAb 1B11 has been characterized as recognizing the activation-associated glycoform of murine CD43, a heavily O-glycosylated protein implicated in leukocyte homing. When hemopoietic cells from CD43−/− mice were stained with 1B11, CD43-independent binding of 1B11 was observed on peripheral CD8 T cells and at low levels on thymocytes, while no binding was detected on CD4 T cells, B cells, or bone marrow cells. Levels of 1B11 staining were comparable in lymph node CD8+ T cells from both CD43−/− mice and CD43+/+ mice. We sought to identify the CD43-independent target of 1B11 expressed on CD8 T cells. Previous work had demonstrated that neuraminidase treatment of lymph node cells (LNC) enhanced 1B11 binding on CD43+/+ LNC; this enhancement was also observed in CD43−/− LNC. We show that neuraminidase-enhanced 1B11 binding in CD43−/− LNC and EL4 thymoma cells is CD43 independent and that 1B11 detects a novel target of apparent mass of ∼200 kDa identified as a hyposialylated form of CD45RB preferentially expressed on peripheral CD8, but not CD4, T cells. Our data also show that the recognition of CD43 and CD45RB by 1B11 is differentially affected by O-linked glycosylation and sialic acid. Whereas 1B11 recognition of CD43 on activated T cells required both core 2 O-glycan branching and sialic acid, 1B11 recognition of CD45 only occurred in the absence of both core 2 glycosylation and sialic acid.