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I Förster

Publications and source records attributed to I Förster.

At least 19 recordsLinked to original sources
PubMed1999

The murine beta-chemokine TARC is expressed by subsets of dendritic cells and attracts primed CD4+ T cells.

To investigate specific properties of dendritic cells (DC) which are not shared by other antigen-presenting cells, we compared gene expression patterns of mouse DC and macrophages by differential mRNA display. One of the cDNA identified coded for a murine homolog of the human beta-chemokine, thymus and activation-regulated chemokine (TARC). The gene is expressed in a subset of bone marrow-derived DC and is up-regulated after lipopolysaccharide (LPS) stimulation. In vivo, murine TARC (mTARC) is constitutively expressed by thymic DC, lymphnode DC and CD11c+ cells in the lung. No expression was detected in bone marrow-derived macrophages and LPS-activated B cells. Recombinant mTARC has no chemoattractant activity on naive peripheral CD4+ T cells. In contrast, mTARC induced migration of primed ovalbumin-specific CD4+ T cells with a preference for Th2 cells during the early phase of the T cell response. These observations suggest that mTARC directs migration of antigen-experienced T helper cells to DC in lymphoid as well as in non-lymphoid organs.

Amino Acid Sequence↗
PubMed1999

Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of Stat3 in macrophages and neutrophils.

We have generated mice with a cell type-specific disruption of the Stat3 gene in macrophages and neutrophils. The mutant mice are highly susceptible to endotoxin shock with increased production of inflammatory cytokines such as TNF alpha, IL-1, IFN gamma, and IL-6. Endotoxin-induced production of inflammatory cytokines is augmented because the suppressive effects of IL-10 on inflammatory cytokine production from macrophages and neutrophils are completely abolished. The mice show a polarized immune response toward the Th1 type and develop chronic enterocolitis with age. Taken together, Stat3 plays a critical role in deactivation of macrophages and neutrophils mainly exerted by IL-10.

Animals↗
PubMed1999

Conditional gene targeting in macrophages and granulocytes using LysMcre mice.

Conditional mutagenesis in mice has recently been made possible through the combination of gene targeting techniques and site-directed mutagenesis, using the bacteriophage P1-derived Cre/loxP recombination system. The versatility of this approach depends on the availability of mouse mutants in which the recombinase Cre is expressed in the appropriate cell lineages or tissues. Here we report the generation of mice that express Cre in myeloid cells due to targeted insertion of the cre cDNA into their endogenous M lysozyme locus. In double mutant mice harboring both the LysMcre allele and one of two different loxP-flanked target genes tested, a deletion efficiency of 83-98% was determined in mature macrophages and near 100% in granulocytes. Partial deletion (16%) could be detected in CD11c+ splenic dendritic cells which are closely related to the monocyte/macrophage lineage. In contrast, no significant deletion was observed in tail DNA or purified T and B cells. Taken together, LysMcre mice allow for both specific and highly efficient Cre-mediated deletion of loxP-flanked target genes in myeloid cells.

Alleles↗
PubMed1998

Residual MHC class II expression on mature dendritic cells and activated B cells in RFX5-deficient mice.

Patients with major histocompatibility complex class II (MHC-II) deficiency are known to carry mutations in either the RFX complex or the trans-activator CIITA. While the pivotal role of CIITA for MHC-II gene transcription is supported by the essential absence of MHC-II molecules in CIITA-deficient mice, we demonstrate here that RFX5-/- mice retain expression of MHC-II in thymic medulla, mature dendritic cells, and activated B cells. Nevertheless, RFX5-/- mice develop a severe immunodeficiency due to the lack of MHC-II in thymic cortex, failure of positive selection of CD4+ T cells, and absence of MHC-II on resting B cells and resident or IFNgamma-activated macrophages. This differential requirement for CIITA and RFX5 in subsets of antigen-presenting cells may be specific for the mouse; it may, however, also exist in humans without having been noticed so far.

Animals↗
PubMed1996

Peripheral tolerance of CD4 T cells following local activation in adolescent mice.

In addition to thymic T cell selection, post-thymic mechanisms of tolerance induction are required to eliminate autoreactive T cells with specificities for peripheral self antigens. While CD8+ T cells can recognize their target antigen on a wide variety of cell types, CD4+ T cells generally depend on the presence of specialized antigen-presenting cells. Because of this fundamental difference in antigen recognition peripheral tolerance of CD4+ T cells appears more difficult to achieve than of CD8+ T cells. Utilizing T cell receptor (TCR)-transgenic mice in which CD4+ T cells specific for a pancreatic beta cell neoantigen (the simian virus 40 T antigen) are constantly generated at low frequency, we have now established a mouse model of peripheral, tissue-specific CD4+ T cell tolerance. In these animals, tolerance is preceded by a phase of activation of the autoreactive T cells as characterized by up-regulation of CD69 and CD44, and down-regulation of the L-selectin lymph node homing receptor. T antigen-specific T cells bearing this phenotype can be detected in the local lymphoid environment of the pancreas but not in more remote locations like axillary or inguinal lymph nodes. The proportion of activated, autoreactive T cells is maximal at 2-3 weeks of age, after which these cells are gradually deleted from the peripheral lymphocyte pool. We further demonstrate that deletion of the autoreactive T cells does not occur in TCR-transgenic mice bred to the RAG-1-deficient background in which the transgenic T cells represent the only functional lymphocyte population.

Animals↗
PubMed1995

Limited capacity for tolerization of CD4+ T cells specific for a pancreatic beta cell neo-antigen.

Mice transgenic for SV40 T antigen (Tag) under control of the rat insulin promoter (RIP) develop two alternative immunological phenotypes: tolerance or autoimmunity towards Tag. We utilized the T cell receptor (TCR) genes expressed in a Tag-specific CD4+ cell from an autoimmune RIP-Tag mouse to generate two lines of TCR transgenic mice in which either 10% or 90% of peripheral T cells express the transgenic TCR. When cross-bred to the tolerant RIP1-Tag2 line, mice from the low frequency TCR line showed partial deletion of peripheral Tag-specific T cells and nonresponsiveness of those that remained. In contrast, crossbred mice in which transgenic T cells comprised a majority of the T cell population were nontolerant both in vivo and in vitro. Thus, tolerization of CD4+ T cells specific for a rare self-antigen may fail if too many autoreactive T cells develop.

Animals↗
PubMed1992

T cell-dependent antibody production by Ly-1 B cells.

Through the use of a SCID transfer system, we have demonstrated that under certain conditions, the production of Ig by Ly-1 B cells can be modulated by T cells. This modulation can take the form of enhanced isotype production or isotype-switch induction and to some extent appears to be dependent on the activation state of the T cells. Furthermore we have shown that Ly-1 B cells can mount an idiotypically restricted T cell-dependent immune response to the antigen PC-KLH. This result suggests that the previous failure to observe T cell-dependent responses by Ly-1 B cells has been due to these B cells being "blind" to the antigens used and is not due to some inherent property of these B cells. When one considers the previous reports of the substantial contribution of Ly-1 B cells to the natural serum immunoglobulin levels and the ability of T cells to affect Ig production by Ly-1 B cells documented in this report, it is clear that the interaction of T cells with the Ly-1 B-cell population is important in determining the "natural" serum Ig repertoire of the mouse.

Animals↗
PubMed1992

An explanation for the defect in secretion of IgM Mott cells and their predominant occurrence in the Ly-1 B cell compartment.

Mott cells are a variant form of plasma cell in which the immunoglobulin (Ig), rather than being secreted, accumulates in rough endoplasmic reticulum-derived vesicles called Russell bodies. We have examined the molecular cause of this defect and the in vivo origin of IgM Mott cells. Our examination of the Ig variable region gene sequences of two IgM Mott hybridomas derived from C.B-20 Ly-1 B cells showed all to be germ line. In a series of mix and match transfection experiments, the Mott phenotype was only reconstituted when the original Mott specificity was expressed as an IgM, suggesting that both the specificity and the isotype were critical to the formation of Russell bodies. Based on our finding that Russell body formation was dependent on the Ig isotype being IgM, we suggest that the Mott phenotype is apparent only after differentiation of B cells into plasma cells and that probably the major cause of the IgM Mott phenotype is low-affinity interaction of the Mott Ig with some as yet unknown intracellular component(s) being stabilized by the intrinsic high avidity of the pentameric secreted form of IgM. Consistent with this proposal was the finding that after in vitro lipopolysaccharide (LPS) stimulation of sorted Ly-1 B cells derived from C.B-20 mice, Mott cells represented up to 5% of the IgM plasma cells in the culture. LPS stimulation of conventional B cells also induced the appearance of IgM Mott cells, but at the much reduced level of 0.1%, suggesting that the major, if not the only, source of Mott cells in vivo is the Ly-1 B cell population. A possible causal relationship between the elevated frequency of Mott cells in the Ly-1 B cell-derived LPS blasts and the repertoire selection inherent in the development of these B cells is discussed.

Amino Acid Sequence↗
PubMed1991

Changes in ceruloplasmin activity and lactate concentration in patients at high risk of acute organ system failure.

In 241 critically ill patients at a high risk of acute organ system failure (OSF) the activity of ceruloplasmin (CPL) and the concentration of lactate in blood was measured. In patients with acute OSF the lactate concentration is high, and the CPL activity is lower in comparison with patients without OSF. These changes are particularly distinct in nonsurviving patients with OSF. The results are discussed in connection with the development of a tissue oxygen debt and the decrease of antioxidative capacity of blood.

Adult↗
PubMed1991

Most peripheral B cells in mice are ligand selected.

Using amplified cDNA and genomic libraries, we have analyzed the VH gene repertoire of pre-B cells and various B cell subsets of conventional mice at the level of VH genes belonging to the J558 VH gene family. The sequence data were evaluated on the basis of a newly established list of 67 J558 VH genes that comprise approximately two-thirds of the J558 VH genes of the murine IgHb haplotype. The results of the analysis demonstrate that VH gene utilization in pre-B cells, although biased to some extent by B cell autonomous VH gene selection, scatters over the whole range of J558 VH genes present in the germline. In contrast, in mature, peripheral B cells comprising long-lived mu + delta high B cells as well as Ly-1 B cells, small overlapping sets of germline VH genes are dominantly expressed. The data indicate that the recruitment of newly generated B cells into the long-lived peripheral B cell pool is mediated through positive selection by internal and/or external antigens. Because of the absence of immunoglobulin class switching and somatic hypermutation, this process is different from the selection of memory B cells in T cell-dependent immune responses.

Animals↗
PubMed1991

Dividing cells in bone marrow and spleen incorporate bromodeoxyuridine with high efficiency.

Labeling of dividing cells with the thymidine analogue 5-bromo-2'-deoxyuridine (BrdUrd) has been frequently used to determine the life-span of cells in various lymphocyte subsets. In this study we address the question of whether administration of BrdUrd in vivo allows labeling of proliferating lymphocytes at early as well as later stages of maturation with high efficiency. For this purpose, the proportion of BrdUrd-labeled cells among all cells synthesizing DNA was determined in the bone marrow and spleen of mice that had received a single injection of BrdUrd or, alternatively, had been fed with BrdUrd for 1 week. On the average, 87% of bone marrow and 83% of spleen cells in the S phase of the cell cycle, as determined by DNA content, were labeled with BrdUrd 1.5 h following injection of the drug. We conclude from these data that administration of BrdUrd in vivo allows labeling of the vast majority of the dividing cells in both primary and secondary lymphoid organs and thus represents an efficient method to determine the life-span of lymphoid cells in vivo.

Animals↗
PubMed1991

Generation of long-lived B cells in germ-free mice.

In the present study we have addressed the question of whether the composition of the peripheral B cell pool is similar in mice raised under conventional, specific pathogen-free or germ-free breeding conditions. For this purpose, the representation of various B lineage subsets was quantitated by flow cytometry and the lifespan of B cells analyzed by labeling dividing cells with the thymidine analogue 5-bromo-2'-deoxyuridine in vivo. The results indicate that except for an increased fraction of CD45R (B220)dull B lineage cells in the bone marrow and a marginally faster turnover of splenic B cells in germ-free compared to conventional mice, there is no obvious difference in the representation and turnover of B cells in the different kinds of mice. The data indicate that a stable pool of peripheral B cells is generated even in the absence of microbial stimulation.

Animals↗
PubMed1990

Sequence homologies, N sequence insertion and JH gene utilization in VHDJH joining: implications for the joining mechanism and the ontogenetic timing of Ly1 B cell and B-CLL progenitor generation.

Sequence analysis of rearranged VHDJH genes of B lineage cells from various stages of ontogeny indicates that short sequence homologies at the breakpoints of recombination contribute to V region gene assembly. Such homologies are regularly seen at DJH junctions of neonatal pre-B cells, most of which do not contain N sequences. In the same cells, but not at later developmental stages, preferential usage of the JH1 element is observed. After birth, N sequence insertion increases with time and is always more prominent at the VHD border than the DJH border. In pre-B cells from adult animals and in mature B cells, in cases where N sequences were not detectable, sequence homologies at the DJH border were found in only half of the instances. This lower incidence could be due to N sequence addition to one of the recombining DNA ends and/or cellular selection. Inspection of VHDJH junctions for N sequence insertion, sequence homologies at the DJH border and JH1 usage allows the estimation of the timepoint in ontogeny at which particular B cell subsets are seeded into the immune system. Specifically, the present data show that the cells of the Ly1 B cell subset are generated not only neonatally but also beyond the first weeks of life. However, the DJH junctions of the progenitors of chronic B cell leukemias which originate from the same B cell subset resemble those of neonatal pre-B cells, suggesting that these cells have already undergone a transforming event at this early developmental stage.

Animals↗
PubMed1990

The bulk of the peripheral B-cell pool in mice is stable and not rapidly renewed from the bone marrow.

We have reevaluated the in vivo lifespan of B lymphocytes based on incorporation of the thymidine analogue 5-bromo-2'-deoxyuridine into the DNA of dividing cells. To exclude potential alterations in the turnover of B-lineage cells due to the bromodeoxyuridine incorporation, we performed pulse-chase experiments comparing the appearance and disappearance of bromodeoxyuridine-labeled cells over long periods of time. The data consistently show that more than two-thirds of splenic B cells in adult (greater than 2 months old) mice have a lifetime of several weeks or months, whereas a more rapid turnover takes place in young (4 week old) mice. Thus, the peripheral B-cell pool is only slowly renewed after it has been initially built up early in life.

Animals↗
PubMed1989

Flow cytometric analysis of cell proliferation dynamics in the B cell compartment of the mouse.

Using a method which allows simultaneous flow cytometric detection of cell surface markers and 5-bromo-2'-deoxyuridine (BrdU) incorporation, the distribution and proliferative behavior of B lineage subpopulations was studied in intact adult mice. In the bone marrow we could define two subsets of B cells on the basis of differential expression of the pan-B cell marker B220 and of membrane-associated mu and delta immunoglobulin heavy chains. B220dull mu+ delta- B cells were found to emerge from rapidly dividing cells and probably represent B cells recently generated from B220dull mu- pre-B cells. In contrast, only few, if any, of the B220bright mu+ delta+ B cells were labeled with BrdU after a period of 8 days, suggesting that these cells represent long-lived B cells residing in the bone marrow. Analysis of BrdU-incorporation into splenic B cells showed that only 20% of these cells had gone through cell division during the preceding 8 days. Almost none of the B cells in the peritoneum, a large fraction of which belongs to the Ly1 B subset, were labeled with BrdU over a period of 7 days in 8-month-old animals.

Animals↗