bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impaired survival and proliferation in IL-7 receptor-deficient peripheral T cells.
Authors: Maraskovsky E , Teepe M , Morrissey P J , Braddy S , Miller R E , Lynch D H , Peschon J J 
Published: December 2022

Abstract
Mice genetically deficient in IL-7R(alpha) are highly lymphopenic in the peripheral lymphoid organs. The functional competence of T cells that have developed in the absence of an IL-7R signal was investigated. Three important observations were made using several in vitro activation regimens. First, stimulation of T cells from IL-7R -/- mice at limiting dilution with immobilized Abs to CD3, CD4 or CD8, and CD18 revealed a six- to sevenfold reduction in the frequency of clonogenic T cells compared with T cells from IL-7R +/+ mice. IL-7R -/- T cells were also significantly less responsive to alloantigen as well as to receptor-independent stimuli such as PMA and ionomycin. Furthermore, the average clone size of single IL-7R -/- T cells was 50% smaller than that of IL-7R +/+ T cells. These data suggest that the reduced clonogenicity was predominantly due to intrinsic deficiencies in the ability of IL-7R -/- T cells to proliferate upon stimulation. Second, analysis of the kinetics of cell growth of IL-7R -/- T cells revealed that a significant proportion of T cells failed to proliferate within the first 72 h of in vitro stimulation, with the majority undergoing programmed cell death. Third, both clonogenic IL-7 -/- T cells and IL-7R +/+ T cells showed a similar proliferative response in the presence of IL-2 and similar survival kinetics, indicating that a subpopulation of IL-7R -/- T cells is functionally mature. We propose that an absence of IL-7R signaling not only affects T cell development in the thymus, but also results in the accumulation of functionally inactive T cells in the periphery.
Cloning of the mouse fusin gene, homologue to a human HIV-1 co-factor.
Authors: Heesen M , Berman M A , Benson J D , Gerard C , Dorf M E 
Published: December 2022

Abstract
Previous studies have demonstrated that mouse cells do not become infected with HIV-1 despite transfection with human CD4. Recently, a human protein termed "fusin" with characteristics of a seven-transmembrane-spanning receptor was found to be a co-factor required for the entry and fusion of HIV-1 with human CD4-bearing lymphocytes. Thus, cloning of the murine homologue of the human fusin (also termed CXCR-4) gene could provide an important comparative tool for identification of the structures crucial for fusin function. Using degenerate PCR, the mouse homologue of human fusin was cloned from a peritoneal exudate cell cDNA library. The predicted amino acid sequence is 91% identical to human fusin. Twenty-eight of the 37 amino acid differences between mouse and human fusin are located in the ectodomains, suggesting that the intracytoplasmic components that mediate G protein binding and signaling are highly conserved. Northern blot analysis showed a message of 2.2 kb in thymus, spleen, neutrophils, and primary astrocyte cultures. Lymphoid and monocyte cell lines also expressed message for fusin. The coding regions of most chemokine receptors lack introns. In contrast, cloning of genomic DNA for mouse fusin revealed the presence of a 2.3-Kb intron separating the first seven amino acids from the remaining 352 residues. Therefore, the mouse fusin gene has a unique genomic organization compared with other chemokine receptors.
A nine-amino acid peptide from IL-1beta augments antitumor immune responses induced by protein and DNA vaccines.
Authors: Hakim I , Levy S , Levy R 
Published: December 2022

Abstract
The idiotypic determinants of B cell lymphoma provide a tumor-specific Ag and a target for immunotherapy. We have developed several generations of idiotype vaccines that were tested in an animal model, the 38C13 mouse B cell lymphoma. Initially we showed that effective tumor immunity was elicited by the syngeneic Id when it was conjugated to a carrier protein and mixed with an adjuvant. A subsequent generation of Id vaccines eliminated the need for a carrier protein and for an adjuvant by incorporating cytokines into fusion proteins containing the Id. A third generation of vaccines consisting of naked DNA encoding the Id-granulocyte-macrophage colony-stimulating factor (GM-CSF) fusion proteins was equally effective in inducing tumor immunity. To determine whether Ig variable regions, in the absence of constant regions, could be immunotherapeutic in this model, we tested the use of single-chain Fv (scFv). scFv proteins, produced in bacteria, and naked DNA encoding scFv were used in this study. scFv was tested alone or fused to GM-CSF or an immunoenhancing peptide derived from IL-1beta. Here we demonstrate that scFv-GM-CSF was effective only when injected as a protein, not as a DNA vaccine. In contrast, both scFv-IL-1beta peptide fusion protein and naked DNA encoding it induced tumor immunity that protected mice from tumor challenge.
Immunodominance analysis of CTL responses to influenza PR8 virus reveals two new dominant and subdominant Kb-restricted epitopes.
Authors: Vitiello A , Yuan L , Chesnut R W , Sidney J , Southwood S , Farness P , Jackson M R , Peterson P A , Sette A 
Published: December 2022

Abstract
In the present study, a systematic analysis of the influenza (Flu) PR8 determinants recognized by H-2b mice was undertaken. A single Db-restricted immunodominant epitope (NP(366)) was previously known in this system. Twenty-three different Flu PR8-derived peptides that bound either Kb or Db molecules in vitro were identified. Sixteen were immunogenic following peptide immunization of C57BL/6 mice, yet CTL induced by peptide immunization recognized PR8-infected target cells only in the case of the NP(366) and NS2(114) epitopes. Similarly, CTL responses following whole-PR8 virus immunization were detected only for the same two determinants. CTL recognizing these dominant epitopes had high avidity for peptide-pulsed target cells, with 5 to 200 pM of peptide required for 30% specific lysis. In contrast, most (80%) of the remaining epitopes were recognized with lower avidity (30% effective concentration in the range of 0.4-50 nM). Repeated in vitro stimulation of primary CTL cultures revealed one additional Kb-restricted epitope (M1(128)). This peptide bound Kb with high affinity (4.6 nM) and induced CTL that effectively recognized PR8-infected cells. These results suggest that 1) this epitope is produced by natural processing in relatively high amounts and 2) low precursor frequency might be related to the subdominant status of the M1(128) epitope. Taken together, these results illustrate the crucial contributions of MHC-binding capacity, and T cell repertoire availability, to the shaping of the repertoire of CTL specificities for Flu Ag virus.
Peripheral blood mononuclear cells of insulin-dependent diabetic patients respond to multiple islet cell proteins.
Authors: Brooks-Worrell B M , Starkebaum G A , Greenbaum C , Palmer J P 
Published: December 2022

Abstract
Insulin-dependent diabetes (IDDM) results from autoimmune destruction of pancreatic beta cells mediated predominantly by cellular effector mechanisms. To date, investigators have studied a limited number of islet cell proteins stimulatory to T cells. However, before development of clinical IDDM, the majority of the beta cells are impaired or destroyed. Thus, numerous proteins from lysed beta cells would be accessible to the immune system of the patient. Our goal was to investigate the PBMC reactivity of IDDM patients to the full spectrum of fractionated human pancreatic islet cell proteins to determine whether numerous islet cell proteins or a select few would be recognized. We observed that PBMCs from IDDM patients responded reproducibly (mean stimulation index, &gt;2.0) to the proteins in all m.w. regions, whereas the mean stimulation index for controls from all m.w. regions was &lt;2.0. Using three different islet protein preparations, PBMC responses of IDDM patients (n = 30) and controls (n = 39) to the islet cell proteins were significantly different. Dose responses were also demonstrated for the lymphocyte reactivity of the IDDM patients (n = 29) vs controls (n = 56) to the islet cell preparations. Proteins, presumably irrelevant to the IDDM disease process, from a human osteosarcoma cell line and normal human spleen cells did not stimulate PBMCs from IDDM patients or controls. Moreover, IDDM patients and controls responded similarly to mitogens and tetanus toxoid. These studies show that at the time of diagnosis of IDDM, PBMCs from IDDM patients are stimulated by a wide array of islet cell proteins.
Specific clonal T cell accumulation in intestinal lesions of Crohn's disease.
Authors: Nakajima A , Kodama T , Yazaki Y , Takazoe M , Saito N , Suzuki R , Nishino H , Yamamoto K , Silver J , Matsuhashi N 
Published: December 2022

Abstract
The initial cellular events that take place at the outset of autoimmune diseases and that may be the most important in terms of understanding their pathogenesis are poorly understood, especially in humans. This is mainly due to the difficulties in the identification of primary lesions and the accessibility to such material. In this respect, it is noteworthy that the appearance of small reddish erosions, known as aphthoid lesions, is known to be an early event in Crohn's disease. In the present study, accumulation of lesion-specific clonal TCR bands in the intestinal lesions of Crohn's disease patients was demonstrated by means of a highly sensitive method based on single strand conformational polymorphism. Such clonal accumulation was demonstrated in both aphthoid and discrete ulcer lesions. There were several TCR BV bands that were present in both aphthoid lesions and discrete ulcer lesions, but some were specific to the aphthoid lesions. In addition, the same aphthoid lesion-specific/dominant T cell clones were found to be expanded in separate aphthoid lesions of a single patient, and were absent from intervening, non-inflamed mucosa. Some of these bands may represent T cell clones activated primarily at the onset of disease.
Restricted TCR repertoire and long-term persistence of donor-derived antigen-experienced CD4+ T cells in allogeneic bone marrow transplantation recipients.
Authors: Vavassori M , Maccario R , Moretta A , Comoli P , Wack A , Locatelli F , Lanzavecchia A , Maserati E , Dellabona P , Casorati G , Montagna D 
Published: December 2022

Abstract
We investigated the contribution of transfer of Ag-experienced donor T cells to the immune reconstitution of allogeneic bone marrow transplantation (BMT) recipients. To this purpose, we used a combination of cell culture methods to isolate tetanus toxoid (TT)-specific T cell clones, and a sensitive and specific heteroduplex analysis to monitor the presence of a particular clonotype using TCR N region sequences. We document that patients after BMT display a small response to TT, entirely accounted for by few donor-derived clones. These patients show a strong polyclonal response to TT vaccination; however, the T cell clones transferred with the transplant can still be detected within the polyclonal T cell lines for up to at least 5 yr after BMT. We also demonstrate that vaccination of donors with TT before BMT results in a more relevant transfer of Ag-experienced T cells, allowing the recipients to mount a strong polyclonal response without need of vaccination. These findings provide a rationale for vaccinating donors to optimize adoptive transfer of protective T cell immunity into recipients, and suggest the possibility of using preventive T cell adoptive therapy in conjunction with marrow infusion.
Tyrosine phosphorylation of Shc is not required for proliferation or viability signaling by granulocyte-macrophage colony-stimulating factor in hematopoietic cell lines.
Authors: Durstin M , Inhorn R C , Griffin J D 
Published: December 2022

Abstract
The receptor for human granulocyte-macrophage (GM)-CSF (GMR) is a heterodimer, consisting of an alpha-chain (GMR alpha) and a beta-chain (GMR beta). While GMR alpha is capable of binding GM-CSF, GMR beta is necessary for signal transduction. Phosphorylation of one or more tyrosine residues in GMR beta is an early event in signaling. We have recently demonstrated that tyrosine 750 (Y750) in GMR beta is a site of GM-CSF-induced phosphorylation and this site may contribute to the maintenance of cellular viability in response to GM-CSF. To investigate possible contributions made by additional GMR beta cytoplasmic tyrosine residues to receptor function, we mutated other selected tyrosine residues to phenylalanine and tested for any defects in signaling. in the present study, we show that Y577 is required for phosphorylation of Shc and an Shc-associated p140 in response to GM-CSF. Y577 is also required for association of Shc with GRB2. Y577 does not appear to be necessary for GM-CSF-induced proliferation and survival. GMR beta with a mutated Y577 is able to transduce signals leading to the activation of the Raf-1 pathway and the Jak-Stat pathway. Interestingly, mutation of Y750 reduced detectable GM-CSF-induced tyrosine phosphorylation of GMR beta, suggesting that the reduction of Shc phosphorylation associated with that mutant might be actually due to a failure to phosphorylate Y577. These data indicate that the phosphorylation of Shc in response to GM-CSF is not required for proliferation or viability signaling in these cells.
The role of the B7-1a molecule, an alternatively spliced form of murine B7-1 (CD80), on T cell activation.
Authors: Inobe M , Aoki N , Linsley P S , Ledbetter J A , Abe R , Murakami M , Uede T 
Published: December 2022

Abstract
B7 molecules (CD80 (B7-1) and CD86 (B7-2/B70)) on APCs provide costimulatory signals for T cell proliferation. We previously described the presence of an alternatively spliced form of murine CD80 (previously termed MB7-2 and renamed as B7-1a) that completely lacks the second Ig-like domain coded by exon 3 in activated murine B cells. in this study, we first examined whether B7-1a mRNA can be detected in vivo by RNase protection assay. The expression of B7-1a mRNA was only detected in lymphoid organs although the level of expression was lesser than that of CD80 mRNA. However, we demonstrated that the expression of B7-1a mRNA like CD80 mRNA was considerably augmented in spleen cells treated with either LPS in vitro or OVA/CFA conjugate in vivo. We next determined the functional activity of B7-1a using Chinese hamster ovary (CHO) cells transfected by B7 genes. When resting T cells were cocultured with CHO cells expressing B7-1a molecules in the presence of PMA/ionomycin, T cell proliferation was not detected, while CHO cells either expressing CD80 or CD86 could promote the proliferation of resting T cells. in contrast to resting T cells, CHO cells expressing B7-1a could support the proliferation of activated T cells. Thus, costimulatory activity of B7-1a molecules was dependent upon the activation stage of T cells. Therefore the IgV-like region of CD80 contains a critical region for functional interaction with its ligands and can transduce a costimulatory signal for T cell proliferation.
Introduction of exogenous antigens into the MHC class I processing and presentation pathway by Drosophila antennapedia homeodomain primes cytotoxic T cells in vivo.
Authors: Schutze-Redelmeier M P , Gournier H , Garcia-Pons F , Moussa M , Joliot A H , Volovitch M , Prochiantz A , Lemonnier F A 
Published: December 2022

Abstract
The homeodomain of the Antennapedia molecule (AntpHD) spontaneously crosses cellular membranes and can be used to deliver up to 50 additional amino acids to the cytoplasm. We exploited this approach to deliver antigenic peptides to the MHC class I processing and presentation pathway. AntpHD-based fusion peptides expressing the 170-179 HLA-Cw3 CTL epitope (pCw3) were produced in bacteria. Incubation of these fusion peptides with H-2d target cells resulted in efficient delivery to the cytosol as indicated by protease resistance and confocal microscopy. Moreover, this introduction of an exogenous Ag resulted in sensitization of the cell to lysis by a CTL clone specific for the 170-179 HLA-Cw3-derived peptide. Sensitivity of the Ag processing to brefeldin A but not to chloroquine is consistent with the delivery of AntpHD fusion peptides to the conventional class I-associated processing pathway. Immunization of DBA/2 (H-2d) mice with AntpHD pCw3 fusion peptide in the presence of SDS primed H-2Kd-restricted HLA-Cw3-specific CTL. Similar results were obtained with AntpHD fusion peptides expressing the 147-156 influenza nucleoprotein peptide. The strategy outlined in this paper provides a new approach for introducing molecules into the MHC class I Ag-presenting pathway. This approach has clear relevance to the design of synthetic peptide-based vaccines.
Self-MHC-restricted peptides recognized by an alloreactive T lymphocyte clone.
Authors: Udaka K , Wiesmüller K H , Kienle S , Jung G , Walden P 
Published: December 2022

Abstract
Alloreactive T lymphocytes are readily detected in unprimed animals although they have never encountered the alloantigen before. This well-established phenomenon is usually explained with the assumption that a self-MHC molecule complexed with a defined peptide resembles the allo-MHC molecule with another peptide and induces the corresponding T cell specificities. Here, for the first time and in support of this hypothesis, self-MHC-restricted peptides are described for a T cell clone that was induced with allo-MHC. The allo-MHC-specific CTL clone 2C was derived from a H-2b mouse and recognizes H-2Ld complexed with the naturally occurring endogenous peptide LSPFPFDL. H-2Kb was shown to be involved in positive selection of its TCR, and peptides associated with this MHC molecule are implicated in the process. To identify such peptides, positional scanning with random peptide libraries combined with an iterative approach was employed. Several active peptides were found and the most efficient, SIYRYYGL, was chosen for further studies. Recognition by 2C of the two MHC-peptide adducts H-2Ld + LSPFPFDL and H-2Kb + SIYRYYGL is mediated by the same TCR and appears to be similarly efficient as concluded from inhibition experiments with an Id-specific Ab. CTLs from SIYRYYGL-primed H-2b mice respond to H-2Ld + LSPFPFDL. This reciprocal cross-reactivity suggests that structural features are shared by the two MHC-peptide complexes.
IL-12 is a central mediator of acute graft-versus-host disease in mice.
Authors: Williamson E , Garside P , Bradley J A , Mowat A M 
Published: December 2022

Abstract
Distinct forms of graft-vs-host disease (GVHD) occur in (C57B1/6 x DBA/2)F1 (BDF1) mice inoculated with either C57B1/6 or DBA/2 parental spleen cells, and it has been suggested that this reflects differential activation of CD4+ Th cell subsets. Transfer of B6 cells produces an acute GVHD, during which an early period of lymphoid hyperplasia precedes immunosuppression, weight loss, and mortality, and a Th1 pattern of cytokines is produced. Conversely, transfer of DBA/2 cells induces a chronic GVHD, in which no weight loss or mortality is observed, but an autoimmune, SLE-like GVHD develops in association with a Th2 pattern of cytokines. Recent work indicates that IL-12 plays a central role in the polarization of Th cell-dependent responses, and here we have examined its role in polarizing GVHD, by administering or depleting IL-12 during the afferent phase of both the acute and chronic forms of GVHD in BDF1 mice. In vivo neutralization of endogenous IL-12 ameliorated acute GVHD, in association with reduced splenic NK cell activity, IFN-gamma production, immunosuppression, weight loss, and mortality. Conversely, administration of exogenous murine rIL-12 exacerbates this disease and converts the chronic GVHD into a lethal acute GVHD-like syndrome. These results indicate that IL-12 plays an important role in the development of acute, but not chronic, GVHD and suggest that differential production of IL-12 early in the disease may underlie these distinct outcomes of the GVHD in BDF1 mice injected with different parental cells.
Requirement of Fas(CD95), CD45, and CD11a/CD18 in monocyte-dependent apoptosis of human T cells.
Authors: Wu M X , Ao Z , Hegen M , Morimoto C , Schlossman S F 
Published: December 2022

Abstract
Our previous studies demonstrated that upon activation, monocytes (Mo) were able to sensitize peripheral blood T (PBT) cells to apoptosis induced by treatment with PMA. However, it is unknown what gene products provide the death signal to the sensitized PBT cells and how activated Mo enable PBT cells to become susceptible to apoptosis. Here, we show that PBT cells, but not Mo, express functional Fas ligand upon treatment with PMA. Moreover, this Mo-dependent T cell apoptosis could be blocked by a Fas-Ig fusion protein, as well as by a nonlytic mAb against Fas molecule. These results strongly suggest involvement of Fas-Fas ligand interaction in the death of PBT cells. Unlike Fas-induced apoptosis, however, Mo-dependent T cell death was completely inhibited by overexpression of the Bcl-2 protein, and PMA alone was sufficient to trigger apoptosis in T cells when Mo were included in culture. Furthermore, anti-CD11a, anti-CD18, or anti-CD45/CD45RA mAbs; could prevent PBT cells from death triggered by PMA plus Mo, suggesting that these Ags participate in the apoptotic process. The participation of CD45RA in the death of PBT cells was further demonstrated by the observation that the J45.01 cell line, a CD45-deficient variant of Jurkat cells, did not undergo apoptosis by this Mo-dependent mechanism. When transfected with cDNA encoding CD45RA, J45.01 cells acquired apoptotic response to PMA stimulation in the presence of Mo to a similar, but lesser, degree than normal Jurkat cells.
Non-T cell-derived IL-4 plays an important role in IgE production induced by antigen resensitization and is resistant to FK506.
Authors: Yamashita M , Yamaoka M , Seki N , Fujii T 
Published: December 2022

Abstract
The present study investigates the role of non-T cell-derived IL-4 in IgE production. It is well known that IL-4 is generally produced by T cells and induces IgE production. We have demonstrated that non-T cells also produce IL-4 in vivo by injection with Ag following passive sensitization of mice with IgE. In contrast to its known potent immunosuppressive effects on T cells, FK506 only partially inhibited IL-4 produced by non-T cells; therefore, FK506 was found to be a useful tool for identifying a cell source of IL-4 production. We used this observation to examine the role of non-T cell-derived IL-4 in IgE production. The production of a high titer of IgE was induced by priming BALB/c mice with Ascaris suum extract and further enhanced by secondary immunization. The IgE production in this model was dependent on IL-4, since both primary and secondary IgE production were completely suppressed by injection with anti-IL-4 Ab. Although primary IgE production was completely inhibited by FK506, secondary IgE production was not inhibited. Furthermore, IL-4 induction in plasma was only partially inhibited by FK506 when the A. suum extract-primed mice were resensitized with Ag. These results indicate that IL-4 produced by non-T cells plays a crucial role in secondary IgE production.