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P Mombaerts

Publications and source records attributed to P Mombaerts.

At least 19 recordsLinked to original sources
PubMed1999

Variable patterns of axonal projections of sensory neurons in the mouse vomeronasal system.

The vomeronasal system mediates pheromonal effects in mammals. We have employed gene targeting technology to introduce mutations in a putative pheromone receptor gene, VR2, in the germline of mice. By generating alleles differentially tagged with the histological markers taulacZ and tauGFP, we show that VR2 is monoallelically expressed in a given neuron. Axons of VR2-expressing neurons converge onto numerous glomeruli in the accessory olfactory bulb. The pattern of axonal projections is complex and variable. This wiring diagram is substantially different from that of the main olfactory system. The projection pattern is disrupted by deleting the coding region of VR2, but an unrelated seven-transmembrane protein, the odorant receptor M71, can partially substitute for VR2.

Alleles↗
PubMed1999

Molecular biology of odorant receptors in vertebrates.

The initial step in olfactory discrimination involves the interaction of odorous ligands with specific receptors on the surface of olfactory sensory neurons. The foundation for a molecular understanding of odor recognition in vertebrates was provided by the identification of a family of genes encoding putative odorant receptors, by Buck & Axel in 1991. Odorant receptor (OR) genes from the largest gene family in the vertebrate genome. This review summarizes progress over the past seven years. Major new insights are: Olfaction is accomplished in vertebrates by a very large number of receptors; olfactory sensory neurons express a small subset of the OR repertoire; in rat and mouse, axons of neurons expressing the same OR converge onto defined glomeruli in the olfactory bulb.

Animals↗
PubMed1996

Visualizing an olfactory sensory map.

We have developed a genetic approach to visualize axons from olfactory sensory neurons expressing a given odorant receptor, as they project to the olfactory bulb. Neurons expressing a specific receptor project to only two topographically fixed loci among the 1800 glomeruli in the mouse olfactory bulb. Our data provide direct support for a model in which a topographic map of receptor activation encodes odor quality in the olfactory bulb. Receptor swap experiments suggest that the olfactory receptor plays an instructive role in the guidance process but cannot be the sole determinant in the establishment of this map. This genetic approach may be more broadly applied to visualize the development and plasticity of projections in the mammalian nervous system.

Animals↗
PubMed1996

Targeting olfaction.

An olfactory sensory neuron most probably expresses a single olfactory receptor gene, out of 1000 choices. Olfactory neurons expressing the same olfactory receptor are distributed over a wide area of the olfactory epithelium, but they project their axons to a few discrete positions in the olfactory bulb, out of 2500 choices. How?

Animals↗
PubMed1995

Characterization of immature thymocyte lines derived from T-cell receptor or recombination activating gene 1 and p53 double mutant mice.

The T-cell receptor (TCR) beta chain is instrumental in the progression of thymocyte differentiation from the CD4-CD8- to the CD4+CD8+ stage. This differentiation step may involve cell surface expression of novel CD3-TCR complexes. To facilitate biochemical characterization of these complexes, we established cell lines from thymic lymphomas originating from mice carrying a mutation in the p53 gene on the one hand and a mutation in TCR-alpha, TCR-beta, or the recombination activating gene 1 (RAG-1) on the other hand. The cell lines were CD4+CD8+ and appeared to be monoclonal. A cell line derived from a RAG-1 x p53 double mutant thymic lymphoma expressed low levels of CD3-epsilon, -gamma, and -delta on the surface. TCR-alpha x p53 double mutant cell lines were found to express complexes consisting of TCR-beta chains associated with CD3-epsilon, -gamma, and -delta chains and CD3-zeta zeta dimers. These lines will be useful tools to study the molecular structure and signal transducing properties of partial CD3-TCR complexes expressed on the surface of immature thymocytes.

Animals↗
PubMed1995

Homeostatic regulation of intestinal epithelia by intraepithelial gamma delta T cells.

Although T cells bearing gamma delta T-cell receptors have long been known to be present in the epithelial lining of many organs, their specificity and function remain elusive. In the present study, we examined the intestinal epithelia of T-cell-receptor mutant mice, which were deficient in either gamma delta T cells or alpha beta T cells, and of normal littermates. The absence of gamma delta T cells was associated with a reduction in epithelial cell turnover and a downregulation of the expression of major histocompatibility complex class II molecules. No such effects were observed in alpha beta T-cell-deficient mice. These findings indicate that intraepithelial gamma delta T cells regulate the generation and differentiation of intestinal epithelial cells.

Animals↗
PubMed1995

Functional analysis of the TCR alpha- beta+ cells that accumulate in the pneumonic lung of influenza virus-infected TCR-alpha-/- mice.

In mice homozygous (-/-) for a targeted TCR-alpha gene disruption, some thymocytes express a cell-surface TCR-beta chain on the cell surface in the absence of a TCR-alpha chain, and a few CD4+CD8- TCR-alpha-beta+ cells accumulate in the peripheral lymphoid organs. We have infected these mutant mice with an influenza A virus to show that large numbers of TCR-beta+ cells (most of which are CD4+) can be retrieved from the pneumonic lung. Both freshly isolated TCR-alpha-beta+ cells and TCR-alpha-beta+ hybridoma cell lines derived from influenza virus-infected mutant mice respond appropriately to stimulation with anti-CD3 epsilon or the Mls-1 superantigen. It thus seems that CD4+ TCR-alpha-beta+ cells in the peripheral lymphoid organs of TCR-alpha mutant mice can signal through their TCR surface complex. However, there are no indications that CD4+ TCR-alpha-beta+ lymphocytes can either recognize a complex between MHC and influenza virus peptide or act as effector or Th cells. The existence and function of such cells in wild-type mice remains to be established.

Animals↗
PubMed1995

Contribution of alpha/beta and gamma/delta T lymphocytes to immunity against Mycobacterium bovis bacillus Calmette Guérin: studies with T cell receptor-deficient mutant mice.

Mutant mice with defined T cell deficiencies were infected with Mycobacterium bovis bacillus Calmette Guérin (BCG) and the relative contribution of alpha/beta T cells and gamma/delta T cells to the host immune response was assessed. Recombinase activating gene (RAG-1)-/- mutants as well as T cell receptor (TcR) beta-/-, but not TcR-delta-/-, mutants succumbed to M. bovis BCG infection and failed to develop granulomatous lesions. Antigen-induced IFN-gamma production by spleen cells in vitro was abrogated in RAG-1-/- mutants and markedly diminished in TcR-beta-/- and TcR-delta-/- mice. Reconstitution experiments suggest that both alpha/beta and gamma/delta T cells are essential for antigen-specific IFN-gamma secretion. Our data formally prove the crucial role of alpha/beta T cells and reveal accessory functions of gamma/delta T cells in optimum immunity against M. bovis BCG.

Animals↗
PubMed1995

Regulation of thymocyte development through CD3: functional dissociation between p56lck and CD3 sigma in early thymic selection.

We studied the extent of functional linkage between CD3 sigma and p56lck in pre-TCR-dependent thymocyte development. Differentiation of DN to DP cells was examined by treatment of RAG2/CD3 sigma and RAG1/p56lck double-deficient mice with anti-CD3 epsilon antibodies. The results suggest that CD3 sigma has no specific role in this maturation step, but may be important for amplification of signaling through the pre-TCR. In contrast, p56lck is the main protein tyrosine kinase associated with signaling through the pre-TCR-CD3 complex. In DP thymocytes, the Ca2+ response to anti-CD3 epsilon was totally abolished in CD3 sigma-I-but only reduced in p56lck-I-mice, and in vivo responses to anti-CD3 epsilon differed from one another. Thus, CD3 sigma and p56lck are functionally not tightly associated and their deficiencies cause distinct developmental defects.

Animals↗
PubMed1995

alpha beta and gamma delta T cells in the immune response to the erythrocytic stages of malaria in mice.

Mice lacking T cells with alpha beta TCR (TCR beta-/-) or gamma delta TCR (TCR delta-/-) were infected with the erythrocytic stages of the malaria parasite, Plasmodium chabaudi chabaudi (AS). Mice without gamma delta T cells could control and reduce a primary infection of P. chabaudi with a slight delay in the time of clearance of the acute phase of infection and significantly higher recrudescent parasitaemias compared with control intact mice. TCR delta -/- mice had higher levels of both serum Ig and malaria-specific antibodies of the isotypes IgG3 and IgG1 compared with control mice. TCR beta -/- mice, despite a striking increase in NK1.1+ cells and the presence of gamma delta T cells, were unable to clear their infection. Although the plasma of TCR beta -/- mice contained all Ig isotypes before and during a primary infection, they were unable to produce significant levels of malaria-specific IgG antibodies, suggesting that in the absence of alpha beta T cells gamma delta T cells are not able to provide efficient help for antibody production.

Animals↗
PubMed1995

Lymphocyte development and function in T-cell receptor and RAG-1 mutant mice.

We have used gene targeting in embryonic stem cells to generate mice with mutations in T-cell receptor (TCR) gene-alpha, TCR-beta, TCR-delta or the Recombination Activating Gene-1 (RAG-1). TCR-alpha or TCR-beta mutant mice are deficient in alpha beta T cells, but still contain gamma delta T cells and B cells. TCR-delta mutant mice are deficient in gamma delta T cells, but still contain alpha beta T cells and B cells. Mice doubly mutant for TCR-beta and TCR-delta do not have any mature T cells, but still have B cells. RAG-1 mutant mice are totally deficient in both mature T cells and B cells. Here, I describe recent studies of thymocyte development in the mutant mice, and I review experiments addressing the function of the immune system of the mutant mice.

Animals↗
PubMed1994

Onset of TCR-beta gene rearrangement and role of TCR-beta expression during CD3-CD4-CD8- thymocyte differentiation.

TCR-beta gene rearrangement or expression is necessary and sufficient for the progression of early alpha beta thymocyte differentiation from the CD3-CD4-CD8- triple negative (TN)3 to the CD4+CD8+ double positive stage. The onset of TCR-beta rearrangement is currently thought to occur gradually. Some thymocytes were reported to be rearranged at the earliest (CD44+CD25-) TN stage, whereas other thymocytes did not initiate TCR-beta rearrangement until the latest (CD44-CD25-) TN stage. Here, we have isolated subsets of TN thymocytes on the basis of surface expression of CD44 and CD25, with c-kit as an additional marker. We present a revised model of early T cell development in which TCR-beta and TCR-gamma rearrangements occur abruptly, at the CD44lowCD25+ c-kitlowTN stage. A high level of c-kit expression defines pro-T cells which have not yet rearranged their TCR genes. Germ-line TCR-beta transcripts, and transcripts of recombination activating genes (RAG)-1 and 2, are detected before TCR-beta gene rearrangement. Analyses of TN thymocytes of RAG-1 mutant mice, and of various TCR mutant and TCR transgenic RAG-1 mutant mice, indicate the existence of a control point at the CD44-CD25+TN stage at which cells expressing a productively rearranged TCR-beta chain are selected for further differentiation.

Animals↗
PubMed1994

Gamma delta T cells contribute to immunity against the liver stages of malaria in alpha beta T-cell-deficient mice.

The functional role of gamma delta T cells (expressing the gamma delta heterodimeric T-cell receptor for antigen) in infectious diseases remains largely unknown. We have therefore attempted to define the possible role of these T cells in the immune response against the various developmental stages of malaria parasites. For this purpose, we monitored the immune response and the development of liver and blood stages of Plasmodium yoelii, a rodent malaria parasite, in immunized and nonimmunized alpha beta T-cell-deficient and gamma delta T-cell-deficient mice. Immunization of alpha beta T-cell-deficient mice with irradiated sporozoites induced an immune response that significantly inhibited the development of the parasite's liver stages. This inhibitory immune response was abolished by an antibody-mediated transient in vivo depletion of gamma delta T cells. Two gamma delta T-cell clones were derived from malaria-immunized alpha beta T-cell-deficient mice. The adoptive transfer of one of these gamma delta T-cell clones to normal mice inhibited the development of liver stages, following sporozoite inoculation. These results provide evidence for gamma delta T-cell-mediated protective immunity against parasites, in the absence of alpha beta T cells. As for the blood phase of the infection, both normal mice and gamma delta T-cell-deficient mice cleared the blood stages of the nonlethal strain of P. yoelii, while alpha beta T-cell-deficient mice failed to control the parasitemia.

Animals↗
PubMed1994

An activated lck transgene promotes thymocyte development in RAG-1 mutant mice.

Expression of the T cell receptor beta (TCR beta) chain is necessary for the transition from the CD4CD8- stage in the major alpha beta thymocyte lineage. The protein tyrosine kinase p56lck has been implicated in the regulation of early thymocyte differentiation and of allelic exclusion at the TCR beta locus. Using mice overexpressing an activated lck transgene and mice with a disruption of the lck gene, we demonstrate that p56lck participates in a pathway that regulates the expansion of the pool of CD4+CD8+ thymocytes to wild-type levels. In addition, p56lck may be involved in the down-regulation of the putative pre-TCR on CD4+CD8+ thymocytes.

Animals↗
PubMed1994

Peripheral lymphoid development and function in TCR mutant mice.

We describe the development and function of the peripheral lymphoid system of mutant mice rendered deficient in either alpha beta or gamma delta T cells via targeting of TCR genes in embryonic stem cells. In the spleen of alpha beta T cell-deficient mice, gamma delta T cells do not compensate in numbers for the lack of alpha beta T cells, but B cells do. alpha beta T cell-deficient mice are unable to mount an antibody response to ovalbumin and do not reject skin allografts. Natural killer cell function is not impaired in any of the mutant mice. TCR mutant mice will prove useful in dissecting differential functions of alpha beta and gamma delta T cells in vivo.

Animals↗
PubMed1993

Restoration of early thymocyte differentiation in T-cell receptor beta-chain-deficient mutant mice by transmembrane signaling through CD3 epsilon.

Thymic repertoire selection requires the expression of the alpha beta CD3 T-cell receptor (TCR) together with the coreceptors CD4 and CD8. The appearance of CD4 and CD8 on thymocytes is the hallmark of a complex maturation step, accompanied by downregulation of the interleukin 2 receptor (IL-2R) alpha chain, arrest of rearrangement (i.e., allelic exclusion) of the TCR beta-chain locus, a burst of cell divisions, and reduction in cell size. This maturation step is inhibited in TCR beta-chain-deficient mouse strains and may depend on surface expression of an immature TCR complex containing CD3 and TCR beta chains but no TCR alpha chain. Here we show that the CD4+8+ double-positive (DP) stage can be induced by treatment of fetal thymic organ cultures with anti-CD3 epsilon monoclonal antibodies in several TCR beta-chain-deficient mouse strains: severe combined immunodeficient (scid) mice, mice carrying a mutation in the recombination activating gene 1 (Rag-1), or mice carrying a deletion in the TCR beta-chain locus itself. These findings suggest that CD3 epsilon is expressed on the thymocyte surface independent of and prior to the TCR beta chain. The data are consistent with the notion that in wild-type mice the DP stage is induced by transmembrane signaling through an immature CD3-TCR beta-chain complex, which can be bypassed by crosslinking of CD3 epsilon alone.

Animals↗
PubMed1993

Spontaneous development of inflammatory bowel disease in T cell receptor mutant mice.

We describe the spontaneous development of inflammatory bowel disease (IBD) in several immunodeficient mouse strains created via gene targeting in embryonic stem cells. Chronic colitis was observed in T cell receptor (TCR) alpha mutant, TCR beta mutant, TCR beta x delta double mutant, or class II major histocompatibility complex (MHC) mutant mice, but not in recombination-activating gene RAG-1 mutant mice or nude mice kept in the same specific pathogen-free animal facility. This clinical pattern suggests that the disease requires the presence of B lymphocytes and the absence of class II MHC-restricted CD4+ alpha beta T cells. IBD in the mutant mice has some of the features of the human disease ulcerative colitis. Based on these results, we suggest that dysfunction of the mucosal immune system may underly the pathogenesis of some types of IBD in humans.

Aging↗