bluuebunny/crossref_metadata_2025_split huggingface dataset:
LeIF: A Recombinant Leishmania Protein That Induces an IL-12-Mediated Th1 Cytokine Profile
Authors: Skeiky Yasir A. W. , Kennedy Mary , Kaufman David , Borges Monamaris M. , Guderian Jeffrey A. , Scholler John K. , Ovendale Pamela J. , Picha Kathleen S. , Morrissey Philip J. , Grabstein Kenneth H. , Campos-Neto Antonio , Reed Steven G. 
Published: January 2023

Abstract
We have evaluated the ability of the Leishmania protein LeIF to influence the Th1/Th2 cytokine responses and the generation of LeIF-specific T cell clones in the absence of adjuvant. We characterized LeIF-specific T cell responses in Leishmania major-infected and uninfected BALB/c mice. These mice develop a strong Th2 response during infection with L. major. When lymph node cells from infected BALB/c mice were stimulated in vitro with LeIF, only IFN-γ (and no detectable IL-4) was found in the culture supernatant. In addition, LeIF down-regulated Leishmania Ag-specific IL-4 production by lymph node cells from infected BALB/c mice. Subsequently, Th responses were evaluated in naive BALB/c mice following immunization with LeIF. T cell clones derived from mice immunized with LeIF preferentially secreted IFN-γ. Finally, to understand the basis for the preferential Th1 cytokine bias observed with LeIF, the ability of LeIF to influence the early cytokine profile was evaluated in splenocytes of SCID mice. We found that LeIF stimulated fresh spleen cells from naive SCID mice to secrete IFN-γ by IL-12/IL-18-dependent mechanisms. The N-terminal half of the molecule (amino acid residues 1–226) maintained the ability to stimulate IFN-γ from splenocytes of SCID mice. Finally, we also demonstrated that LeIF was able to provide partial protection of BALB/c mice against L. major. Thus, our results suggest the potential of LeIF as a Th1-type adjuvant and as a therapeutic and prophylactic vaccine Ag for leishmaniasis when used with other leishmanial Ags.
Differential Effects of CD28 Costimulation on HIV Production by CD4+ Cells
Authors: Barker Edward , Bossart Katharine N. , Levy Jay A. 
Published: January 2023

AbstractWe have observed that CD28 costimulation of CD4+ cells can have differential effects on HIV replication. Triggering the CD28 molecule on peripheral blood CD4+ cells during stimulation with anti-CD3 Abs enhances virus production following acute infection with HIV. Endogenous virus production in CD4+ cells from HIV-infected individuals is also increased by this procedure. The enhanced virus production occurs equally when anti-CD28 Abs and soluble forms of the natural ligands for CD28, CD80Ig, and CD86Ig are used to trigger CD28 on CD4+ cells during stimulation. This increased virus replication is observed only when the source of CD28 costimulation is removed immediately after stimulation and before infection. Continual exposure of CD4+ cells to anti-CD3 and CD28 Ab beads following acute infection prevents virus production. These findings may have relevance to therapeutic approaches aimed at inhibiting HIV replication by CD28 costimulation.
Soluble IL-6 Receptor Potentiates the Antagonistic Activity of Soluble gp130 on IL-6 Responses
Authors: Müller-Newen Gerhard , Küster Andrea , Hemmann Ulrike , Keul Radovan , Horsten Ursula , Martens Astrid , Graeve Lutz , Wijdenes John , Heinrich Peter C. 
Published: January 2023

AbstractSoluble receptors for several cytokines have been detected in body fluids and are believed to modulate the cytokine response by binding the ligand and thereby reducing its bioavailability. In the case of IL-6, the situation is more complex. The receptor consists of two components, including a ligand-binding α-subunit (IL-6R, gp80, or CD126), which in its soluble (s) form (sIL-6R) acts agonistically by making the ligand accessible to the second subunit, the signal transducer gp130 (CD130). Soluble forms of both receptor subunits are present in human blood. Gel filtration of iodinated IL-6 that had been incubated with human serum revealed that IL-6 is partially trapped in IL-6/sIL-6R/sgp130 ternary complexes. sgp130 from human plasma was enriched by immunoaffinity chromatography and identified as a 100-kDa protein. Functionally equivalent rsgp130 was produced in baculovirus-infected insect cells to study its antagonistic potential on four different cell types. It was found that in situations in which cells lacking membrane-bound IL-6R were stimulated with IL-6/sIL-6R complexes, sgp130 was a much more potent antagonist than it was on IL-6R-positive cells stimulated with IL-6 alone. In the latter case, the neutralizing activity of sgp130 could be markedly enhanced by addition of sIL-6R. As a consequence of these findings, sIL-6R of human plasma must be regarded as an antagonistic molecule that enhances the inhibitory activity of sgp130. Furthermore, in combination with sIL-6R, sgp130 is a promising candidate for the development of IL-6 antagonists.
Treatment with Anti-Granulocyte Antibodies Inhibits the Effector Phase of Experimental Autoimmune Encephalomyelitis
Authors: McColl Shaun R. , Staykova Maria A. , Wozniak Andrzej , Fordham Sue , Bruce Joanna , Willenborg David O. 
Published: January 2023

AbstractEmerging data suggest that polymorphonuclear leukocytes (PMNLs) can play an important role in Ag-dependent immune responses. Therefore, we have assessed the involvement of these cells in the development of an organ-specific autoimmune disease, experimental autoimmune encephalomyelitis (EAE), in the mouse. Depletion of peripheral blood PMNLs beginning day 8 after immunization significantly delayed and in some cases totally prevented the development of clinical EAE in mice. Depletion of PMNLs beginning 1 day before sensitization and continuing until day 7 postimmunization had no effect on the subsequent development of EAE, suggesting that depletion alters the efferent but not the afferent arm of the immune response. In vitro studies showed that lymphoid cells from mice protected from EAE by PMNL depletion beginning on day 8 postsensitization proliferated in response to specific Ag to a level equal to cells from sensitized animals treated with control serum, again indicating that treatment was not affecting the afferent limb of the immune response. Further evidence that PMNL may be necessary in initiating the pathology of EAE was seen in passive transfer experiments where PMNL-depleted recipients of MBP-specific lymphoid effector cells developed EAE much less effectively than did animals treated with control Ab. Taken together, these data indicate that PMNLs play a critical role in the effector phase of the development of the clinicopathologic expression of EAE in mice.
Cutting Edge: Fc Receptor Type I for IgG on Macrophages and Complement Mediate the Inflammatory Response in Immune Complex Peritonitis
Authors: Heller Tanja , Gessner J. Engelbert , Schmidt Reinhold E. , Klos Andreas , Bautsch Wilfried , Köhl Jörg 
Published: January 2023

Abstract
The contributions of Fc receptors (FcRs) for IgG (FcγRs) and complement to immune complex (IC)-mediated peritonitis were evaluated in BALB/c-, C57BL/6-, FcRγ chain-, and FcR type III for IgG (FcγRIII)-deficient mice, backcrossed to the C57BL/6 background. In BALB/c mice, but not in C57BL/6 mice, neutrophil migration was markedly attenuated after complement depletion. In mice lacking FcRγ chain, neutrophil migration was abolished, whereas it was unaffected in FcγRIII-deficient mice. Huge amounts of TNF-α (TNF) were found in the peritoneal exudate of BALB/c and C57BL/6 mice but were absent in mice lacking FcRγ chain or FcγRIII. Surprisingly, a functional inhibition of TNF in BALB/c and C57BL/6 mice had no effect on neutrophil infiltration. These data provide evidence that in IC peritonitis, the activation of FcR type I for IgG on peritoneal macrophages and the activation of the complement cascade, but not the interaction of ICs with FcγRIII and the subsequent release of TNF, initiate the inflammatory response in BALB/c and C57BL/6 mice.
Differential Presentation of an Altered Peptide Within Fetal Central and Peripheral Organs Supports an Avidity Model for Thymic T Cell Development and Implies a Peripheral Readjustment for Activation
Authors: Legge Kevin L. , Min Booki , Pack Christopher , Caprio Jacque , Zaghouani Habib 
Published: January 2023

Abstract
Altered self peptides may drive T cell development by providing avidity of interactions low enough to potentiate positive selection but not powerful enough to trigger programmed cell death. Since the peptide repertoire in both central and peripheral organs is nearly the same, interactions of these peptides with T cells in the thymus would have to be different from those taking place in the periphery; otherwise, T cell development and maturation would result in either autoimmunity or T cell deficiency. Herein, a self and an altered self peptide were delivered to fetuses, and their presentation as well as the consequence of such presentation on T cell development were assessed. The results indicate that the self peptide was presented in both central and peripheral fetal organs and that such presentation abolished T cell responses to both peptides during adult life. However, the altered peptide, although presented in vivo as well as in vitro by splenic cells, was unable to stimulate a specific T cell clone when the presenting cells were of thymic origin and allowed offspring to be responsive to both peptides. These findings indicate that central and peripheral organs accommodate selection and peripheral survival of T cells by promoting differential altered peptide presentation.
Lymphoproliferative Disorder in CTLA-4 Knockout Mice Is Characterized by CD28-Regulated Activation of Th2 Responses
Authors: Khattri Roli , Auger Julie A. , Griffin Matthew D. , Sharpe Arlene H. , Bluestone Jeffrey A. 
Published: January 2023

AbstractMice lacking CTLA-4 die at an age of 2–3 wk due to massive lymphoproliferation, leading to lymphocytic infiltration and destruction of major organs. The onset of the lymphoproliferative disease can be delayed by treatment with murine CTLA4Ig (mCTLA4Ig), starting day 12 after birth. In this study, we have characterized the T cells present in CTLA-4-deficient mice before and after mCTLA4Ig treatment. The T cells present in CTLA-4-deficient mice express the activation markers, CD69 and IL-2R; down-regulate the lymphoid homing receptor, CD62L; proliferate spontaneously in vitro and cannot be costimulated with anti-CD28 mAb consistent with a hyperactivated state. The T cells from CTLA-4-deficient mice survive longer in culture correlating with higher expression of the survival factor, Bcl-xL, in these cells. Most significantly, the CD4+ T cell subset present in CTLA-4-deficient mice secretes high levels of IL-4 and IL-5 upon TCR activation. Treatment of CTLA-4-deficient mice treated with mCTLA4Ig reverses the activation and hyperproliferative phenotype of the CTLA-4-deficient T cells and restores the costimulatory activity of anti-CD28 mAb. Furthermore, T cells from mCTLA4Ig-treated mice are not skewed toward a Th2 cytokine phenotype. Thus, CTLA-4 regulates CD28-dependent peripheral activation of CD4+ T cells. This process results in apoptosis-resistant, CD4+ T cells with a predominantly Th2 phenotype that may be involved in the lethal phenotype in these animals.
The Absence of IL-6 Does Not Affect Th2 Cell Development In Vivo, But Does Lead to Impaired Proliferation, IL-2 Receptor Expression, and B Cell Responses
Authors: La Flamme Anne Camille , Pearce Edward J. 
Published: January 2023

AbstractThe role of IL-6 in Th2 cell differentiation and response development after the injection of eggs from Schistosoma mansoni was investigated using wild-type (WT) and IL-6−/− mice. IL-6 was induced in the lymph nodes (LN) of WT mice within 24 h of egg injection, and IL-4 production by WT LN cells and CD4 T cells isolated 24 h after egg injection and stimulated in vitro was observed. In the absence of IL-6, this early production of IL-4 by LN cells and purified CD4 T cells was not abolished; although the level of IL-4 produced by IL-6−/− LN cells was similar to WT, IL-4 production by purified IL-6−/− CD4 T cells was reduced compared with WT. Despite the difference in CD4 T cell production of IL-4, the development of egg-specific Th2 cells 7 days after egg injection was not affected by the absence of IL-6. Nevertheless, Ab production was impaired and the in vitro proliferative response of whole LN cell populations, CD4 and CD8 T cells, and B cells from IL-6−/− mice was poor compared with WT. The proliferative defect in the IL-6−/− cells correlated with decreased IL-2R expression, and addition of exogenous IL-6 enhanced IL-2R expression as well as proliferation of LN cells from IL-6−/− mice. These studies demonstrate that Th2 differentiation and response development in vivo is not dependent on IL-6, but that Th-dependent and independent B cell responses are. Our results also emphasize the importance of IL-6 for lymphoproliferation, possibly through induction of IL-2R expression.
Regulation of Apoptosis in Mature αβ+CD4−CD8− Antigen-Specific Suppressor T Cell Clones
Authors: Khan Qasim , Penninger Josef M. , Yang Liming , Marra Luciano E. , Kozieradzki Ivona , Zhang Li 
Published: January 2023

Abstract
The regulation of apoptosis in mature CD4+ or CD8+ αβ+ T cells has been well studied. How the survival and death is regulated in peripheral CD4−CD8− (double negative, DN) αβ+ T cells remains unknown. Recent studies suggest that peripheral DN T cells may play an important role in the regulation of the immune responses mediated by CD4+ or CD8+ T cells. Here, we used immunosuppressive DN T cell clones to elucidate the mechanisms involved in the regulation of death and survival of αβ+ DN T cells. The DN T cell clones were generated from the spleen cells of 2C transgenic mice, which express the transgenic TCR specific for Ld and permanently accepted Ld+ skin allografts after pretransplant infusion of Ld+ lymphocytes. We report that 1) the mature DN T cells are highly resistant to TCR cross-linking-induced apoptosis in the presence of exogenous IL-4; 2) Fas/Fas-ligand and TNF-α/TNFR pathways do not play an apparent role in regulating apoptosis in DN T cells; 3) the DN T cells constitutively express a high level of Bcl-xL, but not Bcl-2; 4) both Bcl-xL and Bcl-2 are up-regulated following TCR-cross-linking; and 5) IL-4 stimulation significantly up-regulates Bcl-xL and c-Jun expression and leads to mitogen-activated protein kinase phosphorylation in DN T cells, which may contribute to the resistance to apoptosis in these T cells. Taken together, these results provide us with an insight into how mature DN T cells resist activation-induced apoptosis to provide a long-term suppressor function in vivo.
The TCR ζ-Chain Immunoreceptor Tyrosine-Based Activation Motifs Are Sufficient for the Activation and Differentiation of Primary T Lymphocytes
Authors: Geiger Terrence L. , Leitenberg David , Flavell Richard A. 
Published: January 2023

AbstractThe TCR complex signals through a set of 10 intracytoplasmic motifs, termed immunoreceptor tyrosine-based activation motifs (ITAMs), contained within the γ-, δ-, ε-, and ζ-chains. The need for this number of ITAMs is uncertain. Limited and contradictory studies have examined the ability of subsets of the TCR’s ITAMs to signal into postthymic primary T lymphocytes. To study signaling by a restricted set of ITAMs, we expressed in transgenic mice a chimeric construct containing the IAs class II MHC extracellular and transmembrane domains linked to the cytoplasmic domain of the TCR ζ-chain. Tyrosine phosphorylation and receptor cocapping studies indicate that this chimeric receptor signals T cells independently of the remainder of the TCR. We show that CD4+ and CD8+ primary T cells, as well as naive and memory T cells, are fully responsive to stimulation through the IAs-ζ receptor. Further, IAs-ζ stimulation can induce primary T cell differentiation into CTL, Th1, and Th2 type cells. These results show that the ζ-chain ITAMs, in the absence of the γ, δ, and ε ITAMs, are sufficient for the activation and functional maturation of primary T lymphocytes. It also supports the isolated use of the ζ-chain ITAMs in the development of surrogate TCRs for therapeutic purposes.
Fibroblast-Like Synoviocytes from Rheumatoid Arthritis Patients Have Intrinsic Properties of Follicular Dendritic Cells
Authors: Lindhout Ernst , van Eijk Marco , van Pel Melissa , Lindeman Jan , Dinant Huibert J. , de Groot Cornelis 
Published: January 2023

Abstract
The production of IgG rheumatoid factors in the inflamed synovium of many patients with rheumatoid arthritis (RA) implies that local sites exist where plasma cell precursors undergo isotype switching and affinity maturation by somatic mutation and selection. Lymphonodular infiltrates of the synovium-containing germinal centers (GCs), are candidates to fulfill such function in the rheumatoid patient. It has been suggested that these GCs are organized around, obviously ectopic, follicular dendritic cells (FDCs). The present study attempts to find out whether these putative FDCs 1) are specific for RA, 2) have the same phenotype and functional capacity as FDCs in lymphoid organs, and 3) may locally differentiate from fibroblast-like synoviocytes (FLS). Synovial biopsies from patients with RA versus non-RA, yet arthritic backgrounds, were compared. Cells with the FDC phenotype were found in both RA and non-RA tissues as well as in single cell suspensions thereof. When FLS were cultured in vitro, part of these cell lines could be induced with IL-1β and TNF-α to express the FDC phenotype, irrespective of their RA or non-RA background. By contrast, the FDC function, i.e., stable binding of GC B cells and switching off the apoptotic machinery in B cells, appeared to be the prerogative of RA-derived FLS only. The present data indicate that FDC function of FLS in RA patients is intrinsic and support the idea that synovial fibroblast-like cells have undergone some differentiation process that is unique for this disease.
Differential Induction of Adhesion Molecule and Chemokine Expression by LTα3 and LTαβ in Inflammation Elucidates Potential Mechanisms of Mesenteric and Peripheral Lymph Node Development
Authors: Cuff Carolyn A. , Sacca Rosalba , Ruddle Nancy H. 
Published: January 2023

AbstractLymphotoxin (LT) is a member of the proinflammatory TNF family of cytokines that plays a critical role in the development of lymphoid tissue. It has previously been reported that the presence of the LTα transgene under the control of the rat insulin promoter results in inflammation at the sites of transgene expression. LTα transgene expression results in expression of the adhesion molecules VCAM, ICAM, peripheral node addressin (a marker of peripheral lymph nodes), and mucosal addressin cellular adhesion molecule (a marker of mucosal lymphoid tissue, including mesenteric lymph nodes). In this study to determine the mechanisms by which LT promotes inflammation and lymphoid tissue organization, we analyzed the regulation of expression of adhesion molecules and chemokines in LT transgenic mice. The results demonstrate that LTα3 induces expression of the adhesion molecules VCAM, ICAM, and mucosal addressin cellular adhesion molecule as well as the chemokines RANTES, IFN-inducible protein-10, and monocyte chemotactic protein-1, while LTαβ is required for the induction of peripheral node addressin that may contribute to the recruitment of L-selectinhigh CD44low naive T cells. These data provide candidate mediators of LT-induced inflammation as well as potential mechanisms by which LTα and LTαβ may differentially promote the development of mesenteric and peripheral lymph nodes.
USF/c-Myc Enhances, While Yin-Yang 1 Suppresses, the Promoter Activity of CXCR4, a Coreceptor for HIV-1 Entry
Authors: Moriuchi Masako , Moriuchi Hiroyuki , Margolis David M. , Fauci Anthony S. 
Published: January 2023

AbstractTranscription factors USF1 and USF2 up-regulate gene expression (i.e., HIV-1 long terminal repeats) via interaction with an E box on their target promoters, which is also a binding site for c-Myc. The c-Myc oncoprotein is important in control of cellular proliferation and differentiation, while Yin-Yang 1 (YY1) has been shown to control the expression of a number of cellular and viral genes. These two proteins physically interact with each other and mutually inhibit their respective biological functions. In this study, we show that USF/c-Myc up-regulates, while YY1 down-regulates the promoter activity of CXCR4, a coreceptor for T cell-tropic HIV-1 entry. We have identified an E box around −260 and a YY1 binding site around −300 relative to the transcription start site. Mutation of the E box abolished USF/c-Myc-mediated up-regulation of CXCR4 promoter activity, and mutation of the YY1 binding site was associated with unresponsiveness to YY1-mediated inhibition. These data suggest that USF/c-Myc and YY1 may play an important role in the HIV-1-replicative cycle, by modulating both the viral fusion/entry process and viral expression.
IgM Heavy Chain Complementarity-Determining Region 3 Diversity Is Constrained by Genetic and Somatic Mechanisms Until Two Months After Birth
Authors: Shiokawa Satoshi , Mortari Frank , Lima Jose O. , Nuñez César , Bertrand Fred E. , Kirkham Perry M. , Zhu Shigui , Dasanayake Ananda P. , Schroeder Harry W. 
Published: January 2023

Abstract
Due to the greater range of lengths available to the third complementarity determining region of the heavy chain (HCDR3), the Ab repertoire of normal adults includes larger Ag binding site structures than those seen in first and second trimester fetal tissues. Transition to a steady state range of HCDR3 lengths is not complete until the infant reaches 2 mo of age. Fetal constraints on length begin with a genetic predilection for use of short DH (D7-27 or DQ52) gene segments and against use of long DH (e.g., D3 or DXP) and JH (JH6) gene segments in both fetal liver and fetal bone marrow. Further control of length is achieved through DH-specific limitations in N addition, with D7-27 DJ joins including extensive N addition and D3-containing DJ joins showing a paucity of N addition. DH-specific constraints on N addition are no longer apparent in adult bone marrow. Superimposed upon these genetic mechanisms to control length is a process of somatic selection that appears to ensure expression of a restricted range of HCDR3 lengths in both fetus and adult. B cells that express Abs of an “inappropriate” length appear to be eliminated when they first display IgM on their cell surface. Control of N addition appears aberrant in X-linked agammaglobulinemia, which may exacerbate the block in B cell development seen in this disease. Restriction of the fetal repertoire appears to be an active process, forcing limits on the diversity, and hence range of Ab specificities, available to the young.