bluuebunny/crossref_metadata_2025_split huggingface dataset:
The TCR-delta repertoire in human intestine undergoes characteristic changes during fetal to adult development.
Authors: Holtmeier W , Witthöft T , Hennemann A , Winter H S , Kagnoff M F 
Published: December 2022

Abstract
The TCR-delta repertoire in adult human intestine is oligoclonal and unique in each individual. In the present study, changes in the junctional regions of TCR-delta transcripts in human intestine that occur during development from fetal to adult life were used to characterize fundamental changes in the TCR-delta repertoire in the human intestinal tract during ontogeny. At mid-gestation, the fetal repertoire was polyclonal, but limited, in its junctional diversity by the relative lack of N region nucleotide additions and by the frequent formation of coding region joins at regions of short sequence homology. In addition, identical TCRDV2 transcripts that resemble canonical TCR-delta sequences in mice were present in the intestine of different fetuses. In the early period after birth, the intestinal TCR-delta repertoire was polyclonal, and more diverse than the fetal repertoire, with junctional regions that contained extensive N nucleotide additions and frequently were as complex as those of adults. The intestinal TCR-delta repertoire showed increasing restriction with age and, by 14 to 17 yr, the repertoire was oligoclonal and resembled the repertoire of individuals in the sixth to seventh decade. Moreover, the adult TCR-delta repertoire was almost identical at multiple sites throughout the intestine, suggesting a model in which gammadelta T cell clones, selected by ligands in the intestinal tract, undergo expansion and recirculation before lodging throughout the small intestine or colon.
The regulation of p27Kip1 expression following the polyclonal activation of murine G0 T cells.
Authors: Kwon T K , Buchholz M A , Ponsalle P , Chrest F J , Nordin A A 
Published: December 2022

Abstract
Polyclonal activation of murine G0 T cells with immobilized anti-CD3 induces entry into the cell cycle as well as the subsequent cytokine-dependent proliferative response. G0 T cells express high levels of p27Kip1 protein and specific mRNA, which decline rapidly following activation. The decline in the expression of p27Kip1 and sequestering of the inhibitory protein by cdk4 and cdk6 correlated with the increase in cdk2 kinase activity during the G1 phase. Anti-CD3 activation of G0 T cells in the presence of cyclosporin A or rapamycin inhibited the down-regulation of p27Kip1, the cellular levels of the inhibitor remained high, and the cells remained in the G1 phase. PBu2 activation of G0 T cells also did not result in the down-regulation of p27Kip1 and the cells remained in G1. In each instance IL-2 restored the down-regulation of p27Kip1, resulting in a significant reduction in the level of the inhibitor, and stimulated the cells to progress through the cell cycle. Jurkat cells transfected with the p27GL-988 plasmid containing +1 to -988 nt of the p27Kip1 promoter region and subsequently exposed to rIL-2 resulted in a significant reduction in the activity of the p27Kip1 promoter. These findings suggest that in addition to providing the signals required for activated T cells to traverse G1/S, IL-2 also influences the promoter function of p27Kip1, which effectively induces transcriptional down-regulation of the gene.
Overexpression of the heat shock protein 70 enhances the TCR/CD3- and Fas/Apo-1/CD95-mediated apoptotic cell death in Jurkat T cells.
Authors: Liossis S N , Ding X Z , Kiang J G , Tsokos G C 
Published: December 2022

Abstract
To investigate whether the protective effects of the 70-kDa heat shock protein (hsp70) extend to the apoptotic mode of cell death, we transfected Jurkat T cells with the gene for the human hsp70 and challenged the cells with an anti-Fas mAb or with two different murine anti-CD3 mAbs. The anti-Fas mAb-triggered apoptotic cell death and the anti-CD3 mAb-mediated activation-induced cell death were significantly enhanced in the gene-transfected Jurkat cells overexpressing hsp70 compared with the unmanipulated and the vector-transfected cells. On the other hand, the well-established protective effect that this protein offers to the cells was unaffected, as determined by enhanced viability of gene-transfected cells exposed to a lethal heat shock. To investigate the mechanisms that are responsible for the increased susceptibility of the gene-transfected cells to apoptotic death, we studied the TCR/CD3-initiated events that showed a significant down-regulation of the protein tyrosine phosphorylation levels and the cytoplasmic free Ca2+ responses. As for the Fas/Apo-1/CD95-mediated early events, the activity of protein serine/threonine phosphatases was markedly increased in the cells overexpressing hsp70. Our study demonstrates that hsp70 overexpression offers thermoprotection but enhances TCR/CD3- and the Fas-induced apoptotic cell death. This phenomenon is associated with a down-regulation of the Ag receptor-initiated early signal transduction pathways and with an up-regulation of Fas-mediated early metabolic events.
Functional in vivo MHC class II loading by endogenously synthesized glycoprotein during viral infection.
Authors: Oxenius A , Bachmann M F , Mathis D , Benoist C , Zinkernagel R M , Hengartner H 
Published: December 2022

Abstract
MHC class II presentation of antigenic peptides derived from soluble proteins is usually preceded by antigenic uptake via (nonreceptor-mediated) endocytosis by professional APCs, followed by processing in endosomal compartments. Although in vitro alternative pathways for MHC class II loading have been described for certain intracellularly synthesized proteins, the importance of these pathways has not been assessed in vivo. We have shown previously that endogenously produced membrane-associated glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV), a noncytopathic virus, can be presented in vitro on MHC class II molecules in the absence of the invariant chain (Ii), whereas the cytosolic LCMV nucleoprotein (LCMV-NP) failed to be presented under the same conditions. Taking advantage of this system, we analyzed presentation of LCMV-GP and LCMV-NP in vivo in Ii-deficient mice and followed the induced Th cell and B cell responses. At early time points after LCMV infection of li-deficient mice, we found in vivo MHC class II loading exclusively by the endogenously synthesized LCMV-GP, whereas no MHC class II loading by LCMV-NP could be detected. As a direct consequence, LCMV-specific Th cells exhibited initially only LCMV-GP specificity. In contrast, both LCMV-GP- and LCMV-NP-derived epitopes were presented in comparable amounts on APCs upon LCMV infection of normal mice, and LCMV-GP- as well as LCMV-NP-specific Th cells were comparably induced in vivo. Thus, cell internal MHC class II loading pathways are functional in vivo and may become dominant if the usual Ag presentation pathways are hampered.
TCR-gamma genes are rearranged but not transcribed in IL-7R alpha-deficient mice.
Authors: Perumal N B , Kenniston T W , Tweardy D J , Dyer K F , Hoffman R , Peschon J , Appasamy P M 
Published: December 2022

Abstract
IL-7, a cytokine produced by bone marrow and thymic stroma, is a growth factor for B and T lymphocytes very early in their development. The IL-7R is a heterodimer of an alpha-chain that specifically binds IL-7 and the common gamma-chain, gamma(c), which is also a component of the receptors for IL-2, IL-4, IL-9, and IL-15. IL-7 has also been hypothesized to play a role in the differentiation of gammadelta T cells, which is supported by the recent findings that mice deficient in the alpha-chain of the IL-7R (IL-7R alpha -/-) or IL-7 (IL-7 -/-) have a complete absence of gammadelta T cells, but not alphabeta T cells. We show in this work that Vgamma4 and Vgamma6 TCR genes are rearranged, and sterile Vgamma4 and Vgamma6 TCR-gamma transcripts are expressed in IL-7R alpha -/- thymocytes, but these TCR-gamma genes, and Vgamma5, are not transcribed in thymocytes from IL-7R alpha -/- mice. RAG-1 and RAG-2 genes are transcriptionally active in fetal and adult IL-7R alpha -/- thymocytes. The IL-7-inducible transcription factor, STAT5, is not active in the fetal thymus of IL-7R alpha -/- compared with IL-7R alpha +/+ mice. These data point to a specific role for IL-7/IL-7R signaling in regulating the transcriptional activity, possibly mediated by STAT5, of the rearranged TCR-gamma complex during development of gammadelta T cells, and point to mechanistic differences in the regulation of rearrangement of Vgamma4 and Vgamma6 genes vs Vgamma5.
Fas ligand-mediated bystander lysis of syngeneic cells in response to an allogeneic stimulus.
Authors: Smyth M J 
Published: December 2022

Abstract
Using a mouse allospecific lymph node (LN) CTL (H-2b) response to transplanted cells (H-2k), effector cells were shown to lyse C3H/HeJ or L929-Fas (H-2k) target cells in either a perforin-dependent or a Fas ligand (FasL)-dependent manner. C3H/HeJ.lpr targets or L929 targets lacking Fas were not sensitive to these effectors generated in perforin-deficient (Po) mice. By contrast, C3H/HeJ.lpr target cells and L929 were as responsive as C3H/HeJ and L929-Fas targets to the effectors generated in perforin wild-type (P+/+) mice. To measure potential bystander lysis in allogeneic responses, these same effector LN from either C57BL/6 P+/+ or P(o) mice were examined for lysis of C3H/HeJ (or C3H/HeJ.lpr) or L929-Fas (or L929) cocultured with 51Cr-labeled C57BL/6 (H-2b) target cells. Bystander lysis of C57BL/6 targets was observed only in those allogeneic responses where FasL was the defined mechanism of lysis. By contrast, perforin-mediated lysis was restricted by allo-recognition. Syngeneic (H-2b) targets that were not sensitive to Fas-mediated lysis were not lysed in a bystander fashion. Depletion of subsets of LN Po effectors (b anti-k) demonstrated that CD4+ T cells were primarily responsible for FasL-mediated direct and bystander lysis. FasL-mediated bystander lysis was also observed in H-2k anti-b reactions, except when the effectors were FasL mutant (gld). These data suggest that CTL responses to foreign Ag may evoke a certain amount of collateral damage to local host Fas-sensitive cells.
Contribution of the complement control protein modules of C2 in C4b binding assessed by analysis of C2/factor B chimeras.
Authors: Xu Y , Volanakis J E 
Published: December 2022

Abstract
To identify the complement control protein (CCP) module(s) of C2 that are required for C4b recognition, we constructed a panel of C2/factor B chimeras by substituting intact or partial factor B CCP modules for the corresponding ones of C2. Epitope mapping indicated that the anti-C2b mAb 3A3.3, which inhibits binding of C2 to C4b, reacts with the second CCP of C2 and similarly the anti-Ba mAb HA4-1A, which inhibits binding of factor B to C3b, reacts with the second CCP of factor B. The hemolytic activity of the chimeras CP1, CP2, and CP3a containing CCP1, CCP2, and a fragment of CCP3 of factor B, respectively, was substantially decreased compared with that of wild-type C2. The CP3 and CP1-3 chimeras, in which CCP3 and all three CCP modules of factor B, respectively, were substituted, had no hemolytic activity. Loss of activity could be attributed to the resistance of these two chimeras to C1s cleavage, which was probably due to conformational changes of the cleavage site. The combined results indicate that all three CCP modules of C2 contribute structural elements to the C4b-binding site of C2b. This site has been shown previously to be necessary for the initial binding of C2 to C4b which leads to the formation of the classical pathway C3 convertase.
IL-15 enhances immune functions during HIV infection.
Authors: Chehimi J , Marshall J D , Salvucci O , Frank I , Chehimi S , Kawecki S , Bacheller D , Rifat S , Chouaib S 
Published: December 2022

Abstract
IL-15, a new cytokine primarily produced by macrophages, has been shown to exhibit several functional properties shared with IL-2. Treatment of PBMC from HIV-infected patients with IL-15 resulted in an increase in NK cell cytotoxicity to levels similar to those of untreated PBMC from healthy donors. This effect is independent of several well-characterized regulatory cytokines, as it is not prevented by Abs that neutralize IFNs, TNF-alpha, IL-2, or IL-12. Enhanced cytotoxicity was accompanied by a significant increase in expression of cytotoxic granules. IL-15 enhanced the proliferative ability in both controls and HIV-seropositive in response to mitogen and recall Ags. Although the addition of IL-15 has a preventive effect on the appearance of spontaneous cell death, this effect was not seen during mitogen-induced apoptosis. The production of IL-15 by PBMC from patients in response to Staphylococcus aureus Cowan strain 1 appeared heterogeneous and was not negatively regulated by cytokines that inhibited IL-12 production. No correlation was found between in vitro HIV infection and IL-15 production, as viral infection had no effect on the ability of monocytes to produce IL-15 in response to S. aureus. Interestingly IL-15 restored the deficient production of IL-12 by PBMC from HIV+ people and had no major effect on modulating viral expression in latently infected cell lines or PBMC from naturally infected people. Taken together, these results suggest a potent immunoregulatory role of IL-15 during HIV infection.
Diminished HIV-specific CTL activity is associated with lower type 1 and enhanced type 2 responses to HIV-specific peptides during perinatal HIV infection.
Authors: Wasik T J , Jagodzinski P P , Hyjek E M , Wustner J , Trinchieri G , Lischner H W , Kozbor D 
Published: December 2022

Abstract
The early development of symptoms and the rapid progression of disease in some vertically infected infants are thought to reflect in part the immaturity of their immune systems. We examined the relationship between HIV-specific CTL activity and the profile of cytokine production induced by mAb to CD3 and HIV envelope (env) peptides P18 and T1 in PBMC derived from 0.6- to 3.6-yr-old children with perinatal HIV infection. Cellular immunity against HIV was demonstrated only during early stages of disease, whereas the responses were either undetectable or at background levels in HIV-infected children with rapidly progressing disease and in uninfected children of HIV+ and HIV- mothers. Levels of IL-2 mRNA in anti-CD3 mAb- and env peptide-induced PBMC varied and were increased in the infected children with high frequencies of HIV-specific CTL precursors. Analysis of IFN-gamma and IL-4 production by CD4+ T cell clones obtained from cultures stimulated with anti-CD3 mAb or the env peptides showed an increased proportion of Th2 and Th0 clones in HIV-infected children with lower HIV-specific CTL activity, whereas children with high CTL activity had increased numbers of Th1 clones. The results of these studies suggest that decreases in CTL activity to the virus might be associated with the induction of a type 2 cytokine response. These findings underline the role of cytokines in the generation of HIV-specific CTL responses and may be important for the development of immunomodulatory and vaccine strategies to interrupt vertical transmission of HIV.
Identification through bioinformatics of two new macrophage proinflammatory human chemokines: MIP-3alpha and MIP-3beta.
Authors: Rossi D L , Vicari A P , Franz-Bacon K , McClanahan T K , Zlotnik A 
Published: December 2022

Abstract
An increasing number of proinflammatory peptides, known as chemokines, are constantly being described and characterized. Because of their proven biologic functions in allergy, AIDS and, in general, inflammatory processes, these proteins have recently gained more attention. In this study we report the identification through bioinformatics of two new human chemokines: MIP-3alpha and MIP-3beta. Both of them belong to the beta- or CC chemokine family. Expression studies indicate that MIP-3alpha is predominantly expressed in lymph nodes, appendix, PBL, fetal liver, fetal lung and several cell lines. However, MIP-3beta expression is restricted to lymph nodes, thymus and appendix. Interestingly enough, both chemokines manifested a pattern of expression strongly regulated by IL-10. In contrast with other CC chemokines, MIP-3beta maps to chromosome 9. Here we show the importance of bioinformatics to discover new molecules with possible therapeutic effects and regulatory functions.
CD8 alphabeta+ TCR alphabeta(intermediate) lymphocytes expressing skewed TCRVbeta repertoire in the liver of aged athymic nu/nu mice.
Authors: Emoto M , Emoto Y , Kaufmann S H 
Published: December 2022

Abstract
Principally, TCRalphabeta cells differentiate and mature in the thymus. However, evidence has accumulated to suggest that some TCRalphabeta cells develop extrathymically. Such cells have been identified in athymic nu/nu mice that are devoid of a functional thymus. They appear relatively late in ontogeny and randomly increase in number as a function of age. Recently, the liver has been suggested as a candidate site for thymus-independent development of T cells. Here we show that CD8alphabeta+ T cells that express TCRalphabeta at intermediate intensity (TCRalpha(beta)int) are preferentially localized in the liver of nu/nu mice. This population encompassed cells expressing lectin cell adhesion molecule-1 and/or IL-2Rbeta and cells lacking either of these surface molecules. The CD8alphabeta+ TCRalpha(beta)int liver lymphocytes in nu/nu mice also differed in their LFA-1 expression marginally, whereas in C57BL/6 mice all CD8alphabeta+ TCRalpha(beta)int liver lymphocytes expressed LFA-1 at low intensity. Although the TCRVbeta repertoire markedly differed among individual animals, the CD8alphabeta+ TCRalpha(beta)int liver lymphocytes in nu/nu mice preferentially used TCRVbeta5 and/or TCRVbeta8. These findings show that CD8alphabeta+ TCRalpha(beta)int cells develop in the liver of nu/nu mice and that they arise randomly.
G(alpha)i2-deficient mice with colitis exhibit a local increase in memory CD4+ T cells and proinflammatory Th1-type cytokines.
Authors: Hörnquist C E , Lu X , Rogers-Fani P M , Rudolph U , Shappell S , Birnbaumer L , Harriman G R 
Published: December 2022

Abstract
Mice with targeted deletion of the G protein G(alpha)i2 develop an inflammatory bowel disease closely resembling ulcerative colitis. To better define disease pathogenesis, the mucosal immune system in G(alpha)i2-deficient mice was studied. Phenotypic analysis of large intestine lamina propria lymphocytes revealed a large increase in memory CD4+ T cells (CD44high, CD45RBlow, CD62Llow). Furthermore, expression of the mucosal homing receptor integrin beta7 was increased on mucosal, but not systemic, CD4+ T cells. Analysis of cytokine production revealed a marked increase in proinflammatory Th1-type cytokines in inflamed colons, as compared with wild-type mice or G(alpha)i2-deficient mice without colitis. Thus, IFN-gamma and IL-1beta levels were increased 13-fold and 30-fold, respectively, with more modest increases in IL-6 levels (5-fold) and TNF levels (2-fold). Inflamed colons of G(alpha)i2-deficient mice also demonstrated increased IL-12 p40 mRNA levels. No increase in IL-2, IL-4, IL-5, and IL-10 was seen. Large intestinal epithelial cells in G(alpha)i2-deficient mice with colitis were found by immunohistochemistry to express increased levels of both MHC class I and class II Ags. Colitis was associated with increased IgG levels (60-fold increase), predominantly IgG2a (135-fold increase), in large but not small intestinal secretions. This was shown by ELISPOT analysis to result from local production within the lamina propria.
Mouse CD38 is down-regulated on germinal center B cells and mature plasma cells.
Authors: Oliver A M , Martin F , Kearney J F 
Published: December 2022

Abstract
Germinal center formation is the result of antigenic stimulation of B cells in a T cell-rich area. B cells cycle through the germinal centers, and a small percentage survive to become plasma cells or memory B cells. The transformation from a mature B cell into a germinal center B cell and finally into a terminally differentiated B cell is not well understood. Human CD38 is highly expressed on both germinal center B cells and plasma cells, and is useful in delineating these B cell subsets and in understanding the signaling events involved in the development of these B cells. To determine whether CD38 expression on activated germinal center B cells and postgerminal center B cells influences germinal center differentiation, we studied the expression of CD38 in the mouse. CD38 is expressed on follicular B cells in the Peyer's patches but is down-regulated on germinal center B cells located within the Peyer's patches. CD38dim/-B220+ germinal center B cells are also found in the spleens of immunized but not control mice, suggesting that Ag-stimulated germinal center formation is involved in the production of CD38dim/-B220+ B cells. Furthermore, mature plasma cells isolated from in vitro LPS cultures do not express CD38, but do contain high levels of cytoplasmic Ig. These results are in contrast to studies in humans in which CD38 is not found on follicular B cells but is highly expressed on germinal center B cells and plasma cells.
Preferential rearrangements of the T cell receptor-delta-deleting elements in human T cells.
Authors: Verschuren M C , Wolvers-Tettero I L , Breit T M , Noordzij J , van Wering E R , van Dongen J J 
Published: December 2022

Abstract
The major part of the TCR-delta locus is flanked by the so-called TCR-delta-deleting elements deltaRec and psi(J)alpha, which preferentially rearrange to each other in human thymocytes. On the basis of our combined Southern blot and PCR analyses, we also identified the prominent deltaRec-Jalpha58 rearrangement and three other preferential deltaRec rearrangements. The latter rearrangements concern deltaRec rearrangements to the Ddelta3, Jdelta1, and Jdelta3 gene segments. These deltaRec rearrangements do not delete the complete TCR-delta locus and are homologous to Vdelta-Jdelta rearrangements, because the majority of their junctional regions contain Ddelta gene segments. In contrast, the prominent deltaRec-psi(J)alpha and deltaRec-Jalpha58 rearrangements, representing approximately 68 and approximately 23% of all deltaRec rearrangements, respectively, are homologous to Valpha-Jalpha rearrangements, because Ddelta gene segments are absent in their junctional regions. Additional PCR analysis of Vdelta-psi(J)alpha and Vdelta-Jalpha58 coding and signal joints revealed also that these rearrangements resemble Valpha-Jalpha rearrangements, except for Vdelta2-psi(J)alpha and Vdelta2-Jalpha58 rearrangements, which resemble Vdelta-Jdelta rearrangements. Our data show that virtually all TCR-delta-deleting rearrangements are Valpha-like, and the high frequency of these rearrangements in the human thymus suggests that most thymocytes use these rearrangements to further differentiate into the TCR-alphabeta lineage. Based on the very low frequency of deltaRec and psi(J)alpha rearrangements in 4% of the T cell acute lymphoblastic leukemia patients (n = 151) and 6% of the T cell lines (n = 26), we hypothesize that rearranged TCR-delta-deleting elements exist for only an extremely short period during thymocyte differentiation, probably due to rapid subsequent Valpha-Jalpha rearrangements.