bluuebunny/crossref_metadata_2025_split huggingface dataset:
IL-12 Reverses Established Antigen-Specific Tolerance of Contact Sensitivity by Affecting Costimulatory Molecules B7-1 (CD80) and B7-2 (CD86)
Authors: Ushio Hiroko , Tsuji Ryohei F. , Szczepanik Marian , Kawamoto Keiko , Matsuda Hiroshi , Askenase Philip W. 
Published: January 2023

AbstractCutaneous painting with reactive haptens induces contact sensitivity (CS) responses that are in vivo examples of T cell immunity. In contrast, high dose i.v. administration of the hapten can induce tolerance. We investigated the effect of IL-12 on reversal of this tolerance and attempted to determine in vitro the mechanism of this reversing effect by measuring proliferation and IFN-γ production by CS effector T cells stimulated with hapten-conjugated APC, and we also measured CS ear swelling in vivo. The in vitro responses of T cells to hapten-APC became absent in tolerized mice, paralleling impaired in vivo CS responses. Addition of IL-12 to cultures manifesting this fully established in vitro tolerance completely restored impaired responses of tolerized T cells. The reversing effects of IL-12 were not blocked by anti-IFN-γ mAb, but were blocked by mAbs against B7-1, more strongly by anti-B7-2, and by both Abs together. Additional in vivo ear-swelling response experiments confirmed the reversing effects of IL-12 on established tolerance. To examine whether the IL-12 effect depended on stimulation of IFN-γ, we directly injected IFN-γ into tolerized mice. This partially mimicked but did not fully reconstitute the effects of IL-12. In summary, IL-12 abrogation of established tolerance of CS may have been partially due to endogenous production of IFN-γ, but appeared mainly due to direct activation of the tolerized T cells by affecting signaling through costimulatory molecules B7-1 and B7-2.
Antibody Binding to Individual Short Consensus Repeats of Decay-Accelerating Factor Enhances Enterovirus Cell Attachment and Infectivity
Authors: Shafren Darren R. , Dorahy Douglas J. , Thorne Rick F. , Kinoshita Taroh , Barry Richard D. , Burns Gordon F. 
Published: January 2023

Abstract
Decay-accelerating factor (DAF), a widely expressed membrane complement-regulatory protein, is utilized as a cellular receptor by many human enteric pathogens. We show here that the binding of two enteroviruses to individual short consensus repeats (SCR) of DAF on the cell surface is greatly augmented by mAb binding to an alternate SCR: Coxsackievirus A21 binding to the SCR1 of DAF is increased by Ab binding to SCR3 and, conversely, Echovirus 7 binding to SCR3 is enhanced severalfold by Ab binding to SCR1. These Ab-induced increases in viral binding also resulted in increased viral infectivity. Using purified soluble DAF in a solid phase assay it was found that Ab binding to SCR1 is increased greatly in the presence of an Ab against SCR3 and, reciprocally, Ab against SCR1 greatly increases Ab binding to SCR3. In contrast to the results obtained with the larger viral particles, however, this reciprocal Ab-induced enhancement of binding is not seen when measuring Ab binding to membrane-bound DAF SCR on the cell surface. These findings provide a possible explanation for functional differences between membrane-bound and soluble DAF with implications for a potential role for DAF-binding molecules in regulating DAF function. This is the first demonstration of enhancement of viral infectivity mediated by Ab against the viral receptor.
Distinct NFAT Family Proteins Are Involved in the Nuclear NFAT-DNA Binding Complexes from Human Thymocyte Subsets
Authors: Amasaki Yoshiharu , Masuda Esteban S. , Imamura Ryu , Arai Ken-ichi , Arai Naoko 
Published: January 2023

AbstractThe nuclear factor of activated T cells (NFAT) is involved in the transcriptional induction of cytokine and other immunoregulatory genes during an immune response. Among four distinct NFAT family members identified to date, mRNAs of NFAT1, NFATc, and NFATx are expressed in the thymus. Here, we report the distribution of these three NFAT family members in human fetal thymocyte subsets and in peripheral mature T cells. We show that NFATx mRNA was expressed in all T lymphocyte subsets tested and was highest in CD4+CD8+ double positive (DP) thymocytes. Conversely, NFAT1 mRNA was preferentially expressed in the mature CD4+ single positive (SP) populations. NFATc mRNA was present at low levels in all subsets but strongly induced upon treatment with phorbol ester and calcium ionophore. Interestingly, we detected NFAT-DNA binding complexes in DP thymocytes, albeit at lower levels than in CD4 SP cells. Corresponding to the mRNA expression, we observed that NFATx was responsible for the NFAT-DNA binding in DP thymocytes. Moreover, this DNA binding was inhibited by cyclosporin A, indicating that NFATx nuclear translocation was regulated by the calcineurin phosphatase in DP thymocytes. For the CD4 SP populations, NFAT1 and NFATc, and to some extent NFATx, were responsible for the NFAT-DNA binding complexes. These results indicate that NFAT family members are differentially regulated during the development of T cells, and that NFATx may play a distinct role in calcineurin-dependent signaling in DP thymocytes.
CKβ-11/Macrophage Inflammatory Protein-3β/EBI1-Ligand Chemokine Is an Efficacious Chemoattractant for T and B Cells
Authors: Kim Chang H. , Pelus Louis M. , White John R. , Applebaum Edward , Johanson Kyung , Broxmeyer Hal E. 
Published: January 2023

AbstractWe examined the functional properties of CKβ-11/MIP-3β/ELC, a recently reported CC chemokine that specifically binds to a chemokine receptor, EBI1/BLR2/CCR7. CKβ-11/MIP-3β/ELC is distantly related to other CC and CXC chemokines in primary amino acid sequence structure. Recombinant human CKβ-11/MIP-3β/ELC expressed from a mammalian cell system showed potent chemotactic activity for T cells and B cells but not for granulocytes and monocytes. An optimal concentration of CKβ-11/MIP-3β/ELC attracted most input T cells within 3 h, a chemotactic activity comparable with that of stromal cell derived factor 1 (SDF-1), a highly efficacious CXC chemokine. CKβ-11/MIP-3β/ELC equally attracted naive CD45RA+ and memory type CD45RO+ T cells. CKβ-11/MIP-3β/ELC also strongly attracted both CD4+ and CD8+ T cells, but the attraction for CD4+ T cells was greater. CKβ-11/MIP-3β/ELC was also a more efficacious chemoattractant for B cells than MIP-1α, a known B cell chemoattractant. CKβ-11/MIP-3β/ELC induced actin polymerization in lymphocytes, and chemotaxis was completely blocked by pertussis toxin showing its receptor, most likely EBI1/BLR2/CCR7, is coupled to a Gαi protein. CKβ-11/MIP-3β/ELC induced calcium mobilization in lymphocytes, which could be desensitized by SDF-1, suggesting possible cross-regulation in their signaling. Human CKβ-11/MIP-3β/ELC attracted murine splenocytes suggesting functional conservation of CKβ-11/MIP-3β/ELC between human and mouse. The efficacy of chemoattraction by CKβ-11/MIP-3β/ELC and tissue expression of its mRNA suggest that CKβ-11/MIP-3β/ELC may be important in trafficking of T cells in thymus, and T cell and B cell migration to secondary lymphoid organs.
HIV-1/Simian Immunodeficiency Virus Infection of Human and Nonhuman Primate Lymphocytes Results in the Migration of CD2+ T Cells into the Intestine of Engrafted SCID Mice
Authors: Donze Hollie Hale , Cummins James E. , Schwiebert Rebecca S. , Kantele Anu , Han Yuncheng , Fultz Patricia N. , Jackson Susan , Mestecky Jiri 
Published: January 2023

AbstractIncreased lymphocytic infiltration of intestinal tissues has been observed in patients infected with HIV-1 and in SIV-infected rhesus macaques. To determine whether HIV-1 and SIV infections influence the homing of human and nonhuman primate PBMC to intestinal tissues, we engrafted SCID mice with human or nonhuman primate PBMC and infected them with either cell-free or cell-associated HIV-1 or SIV. In mice that received both PBMC and virus, human or nonhuman primate CD2+ T cells were found in intestinal tissues, primarily in the intraepithelial lymphocyte compartment and lamina propria. Immunomagnetic sorting revealed that these cells were derived from the CD4+ population. Using gag-specific primers, PCR analysis of these tissues detected the presence of HIV-1 proviral DNA. However, in SCID mice that were engrafted with either human or nonhuman primate PBMC and no HIV-1 or SIV, CD2+ T cells were not detected in intestinal tissues. These results indicate that HIV-1 and SIV can modulate the migratory properties of human and nonhuman primate T cells in the SCID mouse model.
Cutting Edge: IL-12 and IL-18 Differentially Regulate the Transcriptional Activity of the Human IFN-γ Promoter in Primary CD4+ T Lymphocytes
Authors: Barbulescu Karina , Becker Christoph , Schlaak Jörg F. , Schmitt Edgar , Meyer zum Büschenfelde Karl-Hermann , Neurath Markus F. 
Published: January 2023

Abstract
We analyzed the molecular mechanisms by which IL-12 and IL-18 induce transcriptional activity of the IFN-γ promoter in primary human CD4+ T cells. In transfection experiments, we found that IL-18 directly induces IFN-γ promoter activity, whereas significant activation with IL-12 required costimulation with αCD3/CD28. Furthermore, IL-12 caused in vivo protection of a STAT4 (−236) binding site, whereas stimulation with IL-18 or IL-12 plus αCD3/CD28 induced occupancy of a downstream AP-1 site. Mutation of this AP-1 site abrogated both IL-12- and IL-18-mediated promoter activation, whereas mutation of the STAT site inhibited IL-12-dependent activation. These data suggest that both AP-1 and STAT4 are required for IL-12-dependent IFN-γ promoter activity, whereas IL-18 causes direct activation via AP-1. This differential activation of the IFN-γ promoter gives further insights into molecular pathways governing Th1 T cell development and differentiation.
CD8+ Cells Are Not Necessary for Allograft Rejection or the Induction of Apoptosis in an Experimental Model of Small Intestinal Transplantation
Authors: Krams Sheri M. , Hayashi Michihiro , Fox Christine K. , Villanueva Janeth C. , Whitmer Karen J. , Burns Washington , Esquivel Carlos O. , Martinez Olivia M. 
Published: January 2023

AbstractAllospecific CTL can function as cellular effectors of solid organ graft rejection; however, the specific mechanisms of cell damage remain undetermined. In this study we examined the role of CD8+ T cells in apoptosis and rejection of small intestinal allografts. ACI rat intestinal grafts transplanted into Lewis rat recipients showed apoptosis of epithelial crypt cells on day 3 posttransplant as determined by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling staining. By day 7 numerous apoptotic crypt cells were detected in allografts, but were rarely observed in FK506-treated allograft recipients, isografts, or native intestine of allograft recipients. To further investigate the mechanism of rejection, recipient rats were depleted of CD8+ cells by treatment with OX-8 mAbs the day before and the day after transplantation of rat small intestinal allografts. Depletion of CD8+ cells from allograft recipients did not alter the tempo or the histologic features of rejection compared with those in the control (IgG-treated) group. Moreover, there was no difference in the number of apoptotic crypt epithelial cells in the grafts of control and CD8-depleted rats. Reverse transcriptase-PCR analyses determined there were similar levels of transcripts for Fas, Fas ligand, perforin, and granzyme B in control and CD8-depleted allograft recipients. By Western blot it was determined that the levels of Fas ligand protein were increased in the CD8-depleted group compared with those in control and FK506-treated allograft recipients. These data suggest that CD8 cells are not required for tissue injury or apoptotic cell death in small intestine allograft rejection.
Phorbol Esters Induce Differentiation of Human CD34+ Hemopoietic Progenitors to Dendritic Cells: Evidence for Protein Kinase C-Mediated Signaling
Authors: Davis Thomas A. , Saini Abha A. , Blair Patrick J. , Levine Bruce L. , Craighead Nancy , Harlan David M. , June Carl H. , Lee Kelvin P. 
Published: January 2023

Abstract
The intracellular signals that mediate the differentiation of pluripotent hemopoietic progenitors to dendritic cells (DC) are largely undefined. We have found that the phorbol ester PMA by itself induced 47% ± 8.7% of input human CD34+ hemopoietic progenitors to differentiate into cells with morphology and surface Ag phenotype characteristic of DC by day 7 of culture. Functionally, PMA-generated DC processed and presented whole soluble Ag and also induced resting T cell proliferation and Ag-specific CTL effector function. Unlike cytokine-driven DC differentiation, PMA suppressed proliferation and induced cell death (in part via apoptosis) in cells that did not differentiate to DC. The effects of PMA were blocked by inhibitors of protein kinase C activation, suggesting a central role for this signaling molecule. PMA-mediated signaling also induced expression of the RelB transcription factor, an NF-κB family member implicated in DC differentiation. These findings suggest that phorbol esters activate protein kinase C, which then initiates the terminal component of an intracellular signaling pathway(s) involved in the DC differentiation of CD34+ hemopoietic progenitors.
IFN-γ Receptor Deletion Prevents Autoantibody Production and Glomerulonephritis in Lupus-Prone (NZB × NZW)F1 Mice
Authors: Haas Cordula , Ryffel Bernhard , Le Hir Michel 
Published: January 2023

Abstract
(NZB × NZW)F1 female (BW) mice spontaneously develop an autoimmune disease, characterized by the production of autoantibodies (autoAbs) and glomerulonephritis, which can be delayed by neutralizing IFN-γ Abs and accelerated by IFN-γ injections. To define the role of IFN-γ in the pathogenesis of glomerulonephritis, we established a population of BW mice deficient in IFN-γR (BWγR−/−) by repeated crossing; these mice were compared with BWγR+/+ and +/− littermates. Of the BWγR+/+ and +/− mice, 50% showed immune complex glomerulonephritis with heavy proteinuria at 8 mo of age, while only 10% of the BWγR−/− mice were affected at 14 mo. The serum concentration of anti-dsDNA and anti-histone Abs was dramatically reduced in BWγR−/− mice. The role of IFN-γ in promoting class switch to IgG2a and IgG3 could not fully account for the impaired production of anti-dsDNA in BWγR−/− animals since, IgM and IgG1 levels were also reduced. There was a high incidence of B cell lymphoma in the BWγR−/− mice, which might be related to the suppression of autoAb production. Thus, the absence of glomerulonephritis in BWγR−/− mice is likely due to a dramatic yet unexplained effect of the inactivation of IFN-γ signaling on autoAb production.
CTLA-4 Regulates Tolerance Induction and T Cell Differentiation In Vivo
Authors: Walunas Theresa L. , Bluestone Jeffrey A. 
Published: January 2023

Abstract
Cytotoxic T lymphocyte Ag-4 (CTLA-4; CD152) is an important T cell regulatory molecule. In vitro experiments have shown that the blockade of signals through CTLA-4 augments T cell expansion, while CTLA-4 cross-linking results in decreased T cell proliferation due to decreased IL-2 production. However, less is known about the role of CTLA-4 in regulating an ongoing immune response. In this study, we examined the role of CTLA-4 in the expansion, decline, tolerization, and differentiation of T cells following treatment with staphylococcal enterotoxin B (SEB). Anti-CTLA-4 treatment resulted in increased numbers of SEB-reactive T cells and blockade of subsequent tolerance induction. Further examination of the SEB-reactive cells from anti-CTLA-4-treated mice demonstrated that both the CD4+ and CD8+ Vβ8+ T cells produced IL-4, providing evidence that not only do signals through CTLA-4 regulate T cell-tolerizing events, but they also play an important role in the differentiation of T cells in vivo.
Intraepithelial Infiltration by Mast Cells with Both Connective Tissue-Type and Mucosal-Type Characteristics in Gut, Trachea, and Kidneys of IL-9 Transgenic Mice
Authors: Godfraind Catherine , Louahed Jamila , Faulkner Helen , Vink Anne , Warnier Guy , Grencis Richard , Renauld Jean-Christophe 
Published: January 2023

Abstract
IL-9 transgenic mice were analyzed for the presence of mast cells in different tissues. In these mice, increased mast cell infiltration was found in the gastric and intestinal epithelium as well as in the upper airways and kidney epithelium, but not in other organs, such as skin. IL-9 transgenic mast cells do not show signs of massive degranulation such as that found in IL-4 transgenic mice and are not involved in spontaneous pathologic changes. Gastric mast cells showed a phenotype related to connective-type mast cells, since they were stained by safranin, and strong expression of mouse mast cell protease-4 and -5 was found in this organ. However, they also expressed proteases related to the mucosal cell type, such as mouse mast cell protease-1 and -2. In vitro, although IL-9 by itself did not induce mast cell development from bone marrow progenitors, it strongly synergized with stem cell factor for the growth and differentiation of mast cells expressing the same protease pattern as that observed in IL-9 transgenic mice. Since constitutive stem cell factor expression was observed in vivo, and anti-c-Kit Abs inhibited IL-9 transgenic mastocytosis in the gut, this synergistic combination of factors is likely to be responsible for the mastocytosis observed in IL-9 transgenic mice. Taken together, these data demonstrate that IL-9 induces the in vivo amplification of a nonclassical mast cell subset with a mucosal localization but expressing proteases characteristic of both connective tissue-type and mucosal mast cells.
Human Polymorphonuclear Leukocytes Adhere to Complement Factor H Through an Interaction That Involves αMβ2 (CD11b/CD18)
Authors: DiScipio Richard G. , Daffern Pamela J. , Schraufstätter Ingrid U. , Sriramarao Pragda 
Published: January 2023

AbstractThe work presented here demonstrates that human complement factor H is an adhesion ligand for human neutrophils but not for eosinophils. The adherence of polymorphonuclear leukocytes (PMNs) to plastic wells coated with factor H depended on divalent metal ions and was augmented by C5a and TNF-α. PMN adhesion to factor H in the presence or absence of C5a was blocked specifically by mAbs against CD11b or CD18. Affinity purification using factor H Sepharose followed by immunoprecipitation using mAbs to various integrin chains identified Mac-1 (CD11b/CD18) as a factor H binding receptor. The presence of surface bound factor H enhanced neutrophil activation resulting in a two- to fivefold increase in the generation of hydrogen peroxide by PMNs stimulated by C5a or TNF-α. When factor H was mixed with PMNs, 1.4 to 3.8-fold more cells adhered to immobilized heparin or chondroitin A. In addition, augmented adhesion of PMNs was measured when factor H, but not HSA or C9, was absorbed to wells that were first coated with heparin or chondroitin A. The adhesion of PMNs to glycosaminoglycan-factor H was blocked by mAbs to CD11b and CD18. These studies demonstrate that factor H is an adhesion molecule for human neutrophils and suggest that the interaction of factor H with glycosaminoglycans may facilitate the tethering of this protein in tissues allowing factor H to serve as a neutrophil adhesion ligand in vivo.
IFN-γ Limits Macrophage Expansion in MRL-FaslprAutoimmune Interstitial Nephritis: A Negative Regulatory Pathway
Authors: Schwarting Andreas , Moore Kathryn , Wada Takashi , Tesch Gregory , Yoon Hyung-Jin , Kelley Vicki Rubin 
Published: January 2023

AbstractIFN-γ is capable of enhancing and limiting inflammation. Therefore, an increase in IFN-γ in autoimmune MRL-Faslpr mice could exacerbate or thwart renal injury. We have established a retroviral gene transfer approach to incite interstitial nephritis in MRL-Faslpr mice that is rapid, enduring, and circumscribed. Renal tubular epithelial cells (TEC) were genetically modified to secrete macrophage (Mφ) growth factors (CSF-1-TEC, GM-CSF-1-TEC) and infused under the renal capsule. To determine the impact of IFN-γ in Mφ growth factor-incited renal injury, we constructed a MRL-Faslpr IFN-γ-receptor (IFN-γR)-deficient strain. Gene transfer of CSF-1 or GM-CSF incited more severe interstitial nephritis in IFN-γR-deficient than in IFN-γR-intact MRL-Faslpr mice, consisting of an increase of Mφ. To determine the mechanism responsible for the increase in Mφ in IFN-γR-deficient MRL-Faslpr mice, we evaluated Mφ proliferation, apoptosis, and recruitment. Proliferation of bone marrow Mφ from IFN-γR-intact MRL-Faslpr costimulated with CSF-1 or GM-CSF and IFN-γ was reduced twofold, while the IFN-γR-deficient MRL-Faslpr bone marrow Mφ remained stable. Furthermore, we detected more proliferating and fewer apoptotic Mφ within the interstitium in IFN-γR-deficient MRL-Faslpr mice. Using unilateral ureteral ligation we established that IFN-γR signaling does not alter Mφ recruitment into the kidney. Thus, the increase in Mφ elicited by Mφ growth factors in IFN-γR-deficient MRL-Faslpr mice is a result of enhanced proliferation and decreased apoptosis, and is independent of recruitment. Taken together, we suggest that IFN-γ provides a negative regulatory pathway capable of limiting Mφ-mediated renal inflammation.
A Noncomitogenic CD2R Monoclonal Antibody Induces Apoptosis of Activated T Cells by a CD95/CD95-L-Dependent Pathway
Authors: Fournel Sylvie , Robinet Eric , Bonnefoy-Bérard Nathalie , Assossou Olga , Flacher Monique , Waldmann Herman , Bismuth Georges , Revillard Jean-Pierre 
Published: January 2023

AbstractClonal expansion of activated T and B cells is controlled by homeostatic mechanisms resulting in apoptosis of a large proportion of activated cells, mostly through interaction between CD95 (Fas or Apo-1) receptor and its ligand CD95-L. CD2, which is considered as a CD3/TCR alternative pathway of T cell activation, may trigger activation-induced cell death, but the role of CD95/CD95-L interaction in CD2-mediated apoptosis remains controversial. We show here that the CD2R mAb YTH 655.5, which does not induce comitogenic signals when associated with another CD2 mAb, triggers CD95-L expression by preactivated but not resting T cells, resulting in CD95/CD95-L-mediated apoptosis. The critical role of CD95/CD95-L interaction was supported by complete inhibition in the presence of the antagonist CD95 mAb ZB4 and by blocking CD95-L synthesis and surface expression by cycloheximide, cyclosporin A, EGTA, or cytochalasin B. YTH 655.5 was shown to stimulate p56lck phosphorylation and enzymatic activity. However, p56lck activation is not sufficient to trigger apoptosis, because other CD2R and CD4 mAbs that activate p56lck do not induce apoptosis. In conclusion, CD2 can mediate nonmitogenic signals, resulting in CD95-L expression and apoptosis of CD95+ cells.