bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Helminth-Induced Mucosal Th2 Response Alters Nonresponsiveness to Oral Administration of a Soluble Antigen
Authors: Shi Hai Ning , Ingui Christian J. , Dodge Ingrid , Nagler-Anderson Cathryn 
Published: January 2023

AbstractA fascinating feature of the intestinal mucosal immune system is its ability to guard against invasion by pathogens while avoiding a response to the many potential Ags present in food. The phenomenon of systemic tolerance after oral administration of protein Ags is well documented, but the cellular and molecular basis for the observed nonresponsiveness is not fully understood. To gain insight into the role of the mucosal microenvironment in the induction of orally induced nonresponsiveness, we attempted to induce tolerance to OVA in mice primed for a Th2-biased mucosal immune response by infection with the nematode parasite Heligmosomoides polygyrus. We found that oral tolerance for Th1-type responses to OVA is maintained when OVA is fed during the peak of the mucosal immune response to H. polygyrus. Tolerance for Th2 cytokine responses or a Th2-dependent isotype of IgG is not induced in this Th2-biased mucosal environment. Treatment of infected mice with rIL-12 to reverse the Th2 polarity of the parasite-specific immune response restores tolerance of both Th1 and Th2 responses to OVA. We conclude that the polarized Th2 response induced by this enteric infection plays a central role in determining whether or not systemic tolerance is induced. Our results imply that attempts to use oral administration of Ag to suppress systemic immune responses will be influenced strongly by the presence of mucosal infection.
Lymphoproliferative Disease in Human Peripheral Blood Mononuclear Cell-Injected SCID Mice. IV. Differential Activation of Human Th1 and Th2 Lymphocytes and Influence of the Atopic Status on Lymphoma Development
Authors: Coppola Vincenzo , Veronesi Arianna , Indraccolo Stefano , Calderazzo Francesca , Mion Marta , Minuzzo Sonia , Esposito Giovanni , Mauro Daniele , Silvestri Barbara , Gallo Paolo , Falagiani Paolo , Amadori Alberto , Chieco-Bianchi Luigi 
Published: January 2023

AbstractIntraperitoneal transfer of PBMC from EBV+ donors into SCID mice leads to high human Ig levels in mouse serum and B cell lymphoproliferative disease. As these events depend on the activation of coinjected human T cells, we addressed the behavior of the Th1 and Th2 subsets in this model. Production of IFN-γ, but not of Th2 cytokines such as IL-4, was detected in culture supernatants of PBMC stimulated in vitro with mouse splenocytes. Moreover, anti-CD3 stimulation of the human cells recovered from mice brought about IFN-γ, but not IL-4, synthesis; on the other hand, PCR and in situ hybridization analysis of ex vivo-recovered cells disclosed the presence of mRNA for both cytokines following in vitro restimulation, thus suggesting post-transcriptional regulation of IL-4 gene expression. When SCID mice were inoculated with PBMC from atopic donors, whose Th1/Th2 profile displays an imbalance toward Th2 cells, tumor development rates were lower, and tumor latency was higher, compared with those in mice injected with PBMC from normal donors. Isotypic analysis of human Ig in mouse serum showed the exclusive presence of IFN-γ-driven IgG subclasses; in addition, human IgE were low or undetectable in most cases. These findings indicate that following transfer into SCID mice, human Th1 lymphocytes undergo preferential activation, whereas Th2 function is down-regulated. Th1 lymphocytes probably are a major component in promoting EBV+ B cell expansion and tumor development; the individual Th1/Th2 profile could in part account for the as yet unexplained donor variability in tumor generation in this experimental model.
Malaria Elicits Type 1 Cytokines in the Human Placenta: IFN-γ and TNF-α Associated with Pregnancy Outcomes
Authors: Fried Michal , Muga Richard O. , Misore Ambrose O. , Duffy Patrick E. 
Published: January 2023

AbstractPregnant women, especially primigravidas, are highly susceptible to malaria infection, resulting in maternal anemia and low birth weight infants. Because circulating parasitemia is rare in the newborn, the cause of poor fetal outcomes has been unclear. We measured cytokine concentrations in placentas collected from women delivering in urban hospitals in malaria-holoendemic or nonendemic areas of Kenya. Normal placentas displayed a bias toward type 2 cytokines; type 1 cytokines IFN-γ and IL-2 were absent in placentas not exposed to malaria but present in a large proportion of placentas from a holoendemic area. TNF-α and TGF-β concentrations were significantly higher, and IL-10 concentrations significantly lower, in placentas from the holoendemic area. Among primigravidas, placental TNF-α concentrations were significantly higher in the presence of severe maternal anemia, and both IFN-γ and TNF-α were significantly elevated when a low birth weight, rather than normal weight, infant was delivered. We conclude that maternal malaria decreases IL-10 concentrations and elicits IFN-γ, IL-2, and TNF-α in the placenta, shifting the balance toward type 1 cytokines. This is the first demonstration that these placental cytokine changes are associated with poor pregnancy outcomes in humans.
Cutting Edge: CpG Oligodeoxynucleotides Trigger Protective and Curative Th1 Responses in Lethal Murine Leishmaniasis
Authors: Zimmermann Stefan , Egeter Oliver , Hausmann Susanne , Lipford Grayson B. , Röcken Martin , Wagner Hermann , Heeg Klaus 
Published: January 2023

Abstract
Synthetic oligodeoxynucleotides containing CpG dinucleotides (CpG-ODN) mimic the immunostimulatory qualities of bacterial DNA. We asked whether immunostimulation by CpG-ODN predisposes for a commitment toward a Th1 vs a Th2 response in Leishmania major infection, a model for a lethal Th2-driven disease, in BALB/c mice. CpG-ODN induced Th1 effector T cells in vitro and conveyed protective immunity to disease-prone BALB/c mice in vivo. Conversion to a Th1-driven resistant phenotype was associated with IL-12 production and maintained the expression of IL-12R β2-chains. Most strikingly, CpG-ODN were even curative when given as late as 20 days after lethal L. major infection, indicating that CpG-ODN revert an established Th2 response. These findings imply an important role of bacterial DNA and CpG-ODN in the instruction of adaptive immune responses. They also point to the therapeutic potential of CpG-ODN in redirecting curative Th1 responses in Th2-driven disorders.
Thymic Lineage Commitment Rather Than Selection Causes Genetic Variations in Size of CD4 and CD8 Compartments
Authors: van Meerwijk Joost P. M. , Bianchi Teresa , Marguerat Samuel , MacDonald H. Robson 
Published: January 2023

Abstract
During their development, immature CD4+CD8+ thymocytes become committed to either the CD4 or CD8 lineage. Subsequent complete maturation of CD4+ and CD8+ cells requires a molecular match of the expressed coreceptor and the MHC specificity of the TCR. The final size of the mature CD4+ and CD8+ thymic compartments is therefore determined by a combination of lineage commitment and TCR-mediated selection. In humans and mice, the relative size of CD4+ and CD8+ peripheral T cell compartments shows marked genetic variability. We show here that genetic variations in thymic lineage commitment, rather than TCR-mediated selection processes, are responsible for the distinct CD4/CD8 ratios observed in common inbred mouse strains. Genetic variations in the regulation of lineage commitment open new ways to analyze this process and to identify the molecules involved.
Modulation of Naive CD4 T Cell Activation with Altered Peptide Ligands: The Nature of the Peptide and Presentation in the Context of Costimulation Are Critical for a Sustained Response
Authors: Rogers Paul R. , Grey Howard M. , Croft Michael 
Published: January 2023

AbstractAltered peptide ligands containing single amino acid substitutions have the potential to be used for modulating immune function. Using a panel of moth cytochrome c peptides, we demonstrate that different phases of naive CD4 T cell response are alternately modulated depending on altered peptide ligand dose and accessory molecule expression by APC. Weak agonists presented at high concentration, and with costimulation, efficiently induced early phase naive T cell activation as assessed by IL-2R/CD69 expression, but could only promote sufficient IL-2 for a short-lived proliferative response. In contrast, strong agonists and heteroclitic peptides induced early phase T cell activation even at low concentrations with costimulation, and allowed sustained IL-2 secretion and proliferation. In the absence of accessory molecule help, early and late phase activation was impaired with weak agonists, whereas strong agonists partially compensated for a lack of costimulation for early phase activation, and also promoted enhanced IL-2 with sustained proliferation. These studies support the hypothesis that the naive T cell response will be determined by the balance between provision of accessory molecule help and the affinity of peptide/MHC complexes for individual TCRs, and suggest that extended IL-2 production is the main facet of naive CD4 activation that is affected by altering the nature of the peptide.
MHC Class I Is Required for Peripheral Accumulation of CD8+ Thymic Emigrants
Authors: Nešić Dragana , Vukmanović Stanislav 
Published: January 2023

Abstract
MHC molecules influence the fate of T lymphocytes at two important stages of their differentiation. Recognition of self peptide/MHC complexes in the thymus determines whether immature T cells should live and mature into immunocompetent T cells or whether they should die. In the periphery, recognition of Ags presented by MHC molecules induces T cell activation, proliferation, and differentiation into effector/memory T cells. We describe in this work a third role that MHC molecules play in T cell physiology. CD8+ thymic emigrants require presence of MHC class I molecules in the periphery to seed the peripheral lymphoid organs. Numbers of CD8+ T cells are reduced severely in both the thymus and the periphery of β2-microglobulin-deficient (β2m−/−) mice. When grafted with wild-type (β2m+/+) thymic epithelium, immature β2m−/− T cells that populate the graft develop into functional mature CD8+ cells. However, significant numbers of peripheral CD8+ cells in grafted β2m−/− mice can be observed only after injection of MHC class I-expressing cells in the periphery. Thus, naive T cells in the periphery do not passively await antigenic stimulation, but actively engage in interactions with self MHC molecules that may promote their survival.
TCR Usage by Homocysteine-Specific Human CTL
Authors: Chilvers Myo-Myo , Wordsworth Paul , Stubbs Andy , Gao Xiao-Ming 
Published: January 2023

AbstractWe have recently demonstrated that homocysteine can modify HLA class I Ags and induce homocysteine-specific CTL (Hom-CTL) responses in humans. Here, we have investigated TCR usage by Hom-CTL from five patients with ankylosing spondylitis or reactive arthritis. TCR of HLA-A68-restricted Hom-CTL from two unrelated donors share the same TCR Vα, Vβ, and Jβ gene segments (AV4, BV23, and BJ2S1, respectively) with similar third complementarity determining regions (CDR3) of the β-chains. Interestingly, the Vα and Vβ gene segments employed by an HLA-B27-restricted Hom-CTL clone are also closely related to AV4 and BV23, indicating strong selection pressure for AV4, BV23, and related gene products in the homocysteine-specific TCR. An arginine or lysine residue frequently appeared at position α93 in the CDR3 of the TCR α-chains from Hom-CTL restricted by HLA-A68 or -B8. This may suggest a potential salt bridge between the carboxyl group of homocysteine and specific TCR. TCR usage by HLA-B27-restricted Hom-CTL from unrelated individuals appears to be less conserved, although two T cell clones from one individual rearranged the same V gene segments with identical lengths of CDR3. Implications of these data for the molecular mechanisms for homocysteine modification of HLA Ags are also discussed.
Potent Apoptotic Signaling and Subsequent Unresponsiveness Induced by a Single CD2 mAb (BTI-322) in Activated Human Peripheral T Cells
Authors: Dumont Céline , Déas Olivier , Mollereau Bertrand , Hebib Chafika , Giovino-Barry Valérie , Bernard Alain , Hirsch François , Charpentier Bernard , Senik Anna 
Published: January 2023

AbstractManipulation of CD2 molecules with CD2 mAb pairs has been shown to deliver apoptotic signals to activated mature T cells. We show that BTI-322, a CD2 mAb directed at a peculiar epitope of CD2, can trigger on its own the apoptotic death of IL-2-activated peripheral T cells and of OKT3-stimulated T cells, contrasting in this respect with a series of other mouse or rat CD2 mAb. F(ab′)2 fragments were as potent as the whole Ab. BTI-322-induced apoptosis proceeded in a few hours and was independent of the Fas/Fas ligand system. Less than 5 ng/ml of BTI-322, added at the begining of culture, were able to eliminate within 4 days most CD3+ cells from OKT3- and IL-2-stimulated lymphocytes, the only cells remaining being CD16+CD2− NK cells. T cell proliferative responses induced by a mitogenic CD2 mAb pair or by PHA-P (which mainly binds to CD2) were not inhibited by BTI-322. In this case, the apoptotic effect was successfully counteracted by simultaneous enhancement of T cell divisions. Thus, the killing effect of BTI-322 was most effective when T cells were exclusively stimulated through the CD3/TCR complex. Apoptosis of the responding T cells may explain why T cells recovered from a primary MLC performed in the presence of BTI-322 responded to third party cells but not to the primary stimulatory cells. These data constitute the rational basis for the use of BTI-322 for inducing tolerance in human allotransplantation.
Nuclear Factor κB Is Required for Peptide Antigen-Induced Differentiation of a CD4+CD8+ Thymocyte Line
Authors: Ochoa-Garay Jorge , Kaye Jonathan , Coligan John E. 
Published: January 2023

AbstractNF-κB transcription factors are known to regulate the expression of a number of genes involved in T cell activation and function. Some evidence has suggested that they also play a role in T cell development. However, the role of NF-κB in Ag-induced thymocyte differentiation has not been directly addressed to date. Here we critically examine this role by employing DPK, a CD4+CD8+ thymocyte line that undergoes differentiation upon TCR engagement in a process that closely mimics positive selection. Expression of a degradation-resistant form of IκBα in DPK cells results in constitutive inhibition of NF-κB activity. We find that in the absence of NF-κB activity, MHC-peptide-induced differentiation of DPK is blocked. Furthermore, differentiation induced by a nonphysiologic stimulus, anti-TCR Ab, is greatly reduced. Altogether, our data indicate a requirement for NF-κB in the developmental changes associated with positive selection.
Posttranslational Regulation of TCR Vα Allelic Exclusion During T Cell Differentiation
Authors: Alam S. Munir , Gascoigne Nicholas R. J. 
Published: January 2023

Abstract
We have previously shown that phenotypic allelic exclusion of TCR α-chain is functional only in mature thymocytes. A significant proportion of immature thymocytes (TCRlow) express more than one cell surface α-chain, but mature thymocytes (TCRhigh) show phenotypic allelic exclusion and express only a single α-chain. We have analyzed thymocytes for both surface and intracellular α-chain expression and find that the majority of mature thymocytes express a second α-chain intracellularly. This result is predicted by a model in which the developmentally regulated allelic exclusion of the TCR α-chain is caused by competition between α-chains for the β-chain rather than by models in which one α-chain is down-regulated or in which selection favors cells with only a single α-chain species. Changes in the relative amounts of α- and β-chains available for pairing may therefore allow competition between the two α-chains for the β-chain. Peripheral T cells also frequently express second α-chains in the cytoplasm (18–27%), despite a rather low frequency of dual α-chain expression on the cell surface (2–4%). The frequency of nonsurface expressed α-chains is reduced somewhat compared with thymocytes, indicating that an additional level of control of allelic exclusion operates during the maturation of peripheral T cells.
Impaired Macrophage Function and Enhanced T Cell-Dependent Immune Response in Mice Lacking CCR5, the Mouse Homologue of the Major HIV-1 Coreceptor
Authors: Zhou Yuhong , Kurihara Takao , Ryseck Rolf-Peter , Yang Yi , Ryan Carol , Loy James , Warr Glenn , Bravo Rodrigo 
Published: January 2023

AbstractThe CC-chemokine receptor CCR5 has been shown to be the major coreceptor for HIV-1 entry into cells, and humans with homozygous mutation in the ccr5 gene are highly resistant to HIV-1 infection, despite the existence of many other HIV-1 coreceptors. To investigate the physiologic function of CCR5 and to understand the cellular mechanisms of these clinical observations, we generated a CCR5-deficient mouse model (ccr5−/−) by targeted deletion of the ccr5 gene. We found that although developed normally in a pathogen-free environment, CCR5-deficient mice showed reduced efficiency in clearance of Listeria infection and exsert a protective effect aganist LPS-induced endotoxemia, reflecting a partial defect in macrophage function. In addition, CCR5-deficient mice had an enhanced delayed-type hypersensitivity reaction and increased humoral responses to T cell-dependent antigenic challenge, indicating a novel role of CCR5 in down-modulating T cell-dependent immune response.
Induction and Enhancement of FcεRI-Dependent Mast Cell Degranulation Following Coculture with Activated T Cells: Dependency on ICAM-1- and Leukocyte Function-Associated Antigen (LFA)-1-Mediated Heterotypic Aggregation
Authors: Inamura Noriaki , Mekori Yoseph A. , Bhattacharyya Siba P. , Bianchine Peter J. , Metcalfe Dean D. 
Published: January 2023

AbstractActivated mast cells are known to reside in close apposition to T cells in various inflammatory processes. In this regard, we have reported that activated mast cells form heterotypic aggregates with activated lymphocytes. To determine whether this interaction would result in mast cell degranulation, we examined the effect of EL-4, 2B4, or freshly isolated T cells, activated by PMA or immobilized anti-CD3 mAb, on histamine release from murine bone marrow-derived cultured mast cells (BMCMC). Coculturing BMCMC with activated but not with resting T cells resulted in significant histamine release. Also, FcεRI cross-linking-induced degranulation was augmented when BMCMC were cocultured with activated T cells. Supernatants of activated T cells failed to exert the stimulatory effect. Separation of the two cell populations with a porous membrane prevented degranulation, indicating that BMCMC activation was adhesion dependent. Indeed, the kinetics of histamine release paralleled the kinetics of the formation of heterotypic aggregates, which peaked after 12 h of coculture. Introduction of anti-LFA-1 and anti-intercellular adhesion molecule-1 mAb inhibited the adhesion-induced mast cell degranulation. These data suggest a heretofore unrecognized mast cell activation pathway induced by LFA-1/intercellular adhesion molecule-1-mediated heterotypic aggregation with activated T cells.
Posttranslational Modifications Affect the Activity of the Human Monocyte Chemotactic Proteins MCP-1 and MCP-2: Identification of MCP-2(6–76) as a Natural Chemokine Inhibitor
Authors: Proost Paul , Struyf Sofie , Couvreur Mikaël , Lenaerts Jean-Pierre , Conings René , Menten Patricia , Verhaert Peter , Wuyts Anja , Damme Jo Van 
Published: January 2023

Abstract
Chemokines are important mediators in infection and inflammation. The monocyte chemotactic proteins (MCPs) form a subclass of structurally related C-C chemokines. MCPs select specific target cells due to binding to a distinct set of chemokine receptors. Recombinant and synthetic MCP-1 variants have been shown to function as chemokine antagonists. In this study, posttranslationally modified immunoreactive MCP-1 and MCP-2 were isolated from mononuclear cells. Natural forms of MCP-1 and MCP-2 were biochemically identified by Edman degradation and mass spectrometry and functionally characterized in chemotaxis and Ca2+-mobilization assays. Glycosylated MCP-1 (12 and 13.5 kDa) was found to be two- to threefold less chemotactic for monocytes and THP-1 cells than nonglycosylated MCP-1 (10 kDa). Natural, NH2-terminally truncated MCP-1(5–76) and MCP-1(6–76) were practically devoid of bioactivity, whereas COOH-terminally processed MCP-1(1–69) fully retained its chemotactic and Ca2+-inducing capacity. The capability of naturally modified MCP-1 forms to desensitize the Ca2+ response induced by intact MCP-1 in THP-1 cells correlated with their agonistic potency. In contrast, naturally modified MCP-2(6–76) was devoid of activity, but could completely block the chemotactic effect of intact MCP-2 as well as that of MCP-1, MCP-3, and RANTES. Carboxyl-terminally processed MCP-2(1–74) did retain its chemotactic potency. Although comparable as a chemoattractant, natural intact MCP-2 was found to be 10-fold less potent than MCP-1 in inducing an intracellular Ca2+ increase. It can be concluded that under physiologic or pathologic conditions, posttranslational modification affects chemokine potency and that natural MCP-2(6–76) is a functional C-C chemokine inhibitor that might be useful as an inhibitor of inflammation.
Involvement of the IL-2 Receptor γ-Chain (γc) in the Control by IL-4 of Human Monocyte and Macrophage Proinflammatory Mediator Production
Authors: Bonder Claudine S. , Dickensheets Harold L. , Finlay-Jones John J. , Donnelly Raymond P. , Hart Prue H. 
Published: January 2023

AbstractIL-4 has potent anti-inflammatory properties on monocytes and suppresses both IL-1β and TNF-α production. Well-characterized components of the IL-4 receptor on monocytes include the 140-kDa α-chain and the IL-2R γ-chain, γc, which normally dimerize 1:1 for signaling from the receptor. However, mRNA levels for γc were very low in 7-day-cultured monocytes. As mRNA levels for γc declined with culture, so too did the ability of IL-4 to down-regulate LPS-induced TNF-α production. In contrast, IL-4 consistently down-regulated IL-1β production by cultured monocytes. Immunoprecipitation and Western blot analyses demonstrated that 7-day-cultured monocytes do not express the functionally active 64-kDa γc protein. This was associated with decreased STAT6 activation by IL-4. Studies with Abs to γc and an IL-4 mutant that is unable to bind to γc showed that IL-4 can suppress IL-1β but not TNF-α production by LPS-stimulated monocytes in the presence of little or no functioning γc. IL-4 also suppressed IL-1β but not TNF-α production by Mono Mac 6 cells, which express minimal levels of γc. For γc-expressing LPS/PMA-activated U937 cells, IL-4 decreased both TNF-α and IL-1β production. These results suggest that functional γc is not present on in vitro-derived macrophages, and that while some anti-inflammatory responses to IL-4 are lost with this down-regulation of functional γc, others are retained. We conclude that different functional responses to IL-4 by human monocytes and macrophages are regulated by different IL-4 receptor configurations.