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J Penninger

Publications and source records attributed to J Penninger.

32 records · Page 2Linked to original sources
PubMed1993

Requirement for tyrosine kinase p56lck for thymic development of transgenic gamma delta T cells.

The Src-related protein tyrosine kinase p56lck is essential for antigen-specific signal transduction and thymic maturation of T cells that have an alpha beta T cell receptor (TCR), presumably by physical association with CD4 or CD8 molecules. To evaluate the requirement for p56lck in the development of T cells that have gamma delta TCRs, which generally do not express CD4 or CD8, p56lck mutant mice were bred with TCR gamma delta transgenic mice. Few peripheral cells that carried the transgenes could be detected in p56lck-/- mice, although 70 percent of thymocytes were transgenic. Development of transgenic gamma delta+ thymocytes was blocked at an early stage, defined by interleukin-2 receptor alpha expression. However, extrathymic development of CD8 alpha alpha+ TCR gamma delta+ intestinal intraepithelial lymphocytes appeared to be normal. Thus, p56lck is crucial for the thymic, but not intestinal, maturation of gamma delta T cells and may function in thymic development independently of CD4 or CD8.

Animals↗
PubMed1993

In situ analyses of in ovo graft-vs.-host reaction induced by thymic nurse cell lymphocytes.

In both mammalian and avian systems, thymic nurse cells (TNC) have been shown to harbor a heterogeneous population of T lymphocytes (TNC-L) some of which exhibit a postselectional phenotype. By transplanting micromanipulated single chicken TNC onto the chorionallantoic membrane (CAM) of major histocompatibility complex (MHC)-disparate embryos, an experimental system which allows for the detection of lymphocytes with graft-vs.-host (GVH) reactivity, we demonstrate here that TNC enclose lymphocytes that can develop into both CD4+ single-positive (sp) and CD8+ sp, T cell receptor (TcR) alpha beta+, or TcR gamma delta+ cells. This finding was additionally confirmed by serial transfer of primary expanded alloreactive T cells onto the CAM of secondary hosts. All donor TNC-L expressed MHC class II molecules and the interleukin-2 receptor alpha chain in primary and secondary GVH reactions. Furthermore, we observed selective accumulation of CD8+ and TcR gamma delta+ host lymphocytes in the CAM upon the induction of a local GVH reaction, most probably as a consequence of the pathological alteration of the epithelium.

Animals↗
PubMed1993

CD4, CD8 and tyrosine kinases in thymic selection.

Analysis of T-cell development in transgenic and gene-deficient mice suggests that the co-receptor function of CD8 is essential for positive selection. Recent data also demonstrate that the requirement for CD4 and CD8 in negative selection of T cells is not absolute and may be regulated by T-cell receptor affinity for the deleting ligand, an interpretation consistent with the affinity model of thymic selection. In addition to its association with CD4 and CD8, it appears that p56lck is also important during the early stages of thymic development.

Animals↗
PubMed1993

Genetically modified animals and immunodeficiency.

Mouse strains with defined genetic defects engineered by the method of targeted gene disruption and homologous recombination have furthered our understanding of immune functions at the single gene level. More importantly, these mutant 'gene knockout' mice are powerful in vivo tools to dissect the complex mechanisms of lymphocyte development and function, complementing our broadening knowledge of congenital and acquired human immunodeficiencies.

Animals↗
PubMed1992

CD45RA and CD45RBhigh expression induced by thymic selection events.

CD45 is a protein tyrosine phosphatase involved in T and B cell signaling. While peripheral T cells switch CD45 isoforms upon activation, events leading to exon switching during T cell development in the thymus have not been determined. The expression of high molecular weight isoforms of CD45 was examined on thymocytes from nontransgenic and T cell receptor (TCR) transgenic mice. All thymocytes from nontransgenic mice were CD45RB+ as assessed by staining with MB23G2, an anti-CD45RB-specific monoclonal antibody. Interestingly, there was a small population (1-3%) of thymocytes that displayed a higher intensity of staining with MB23G2, CD45RBhigh. CD45RBhigh thymocytes were found in all subsets defined by CD4 and CD8 expression and were also present within the TCR-alpha/beta high population. To analyze whether or not CD45 expression correlated with thymic selection events, expression of CD45RBhigh and a second isoform, CD45RA, was examined on thymocytes from H-Y and 2C TCR transgenic mice and found to correlate with positive and negative selection events but did not occur in nonselecting backgrounds. CD45RA and CD45RBhigh upregulation was also not observed in transgenic mice backcrossed into CD8-deficient mice, a scenario in which there is no positive selection of transgene-expressing thymocytes. These data suggest that modulation of CD45 isoform expression may be involved in thymic selection events.

Animals↗
PubMed1992

CD4 expression is differentially required for deletion of MLS-1a-reactive T cells.

Clonal deletion of thymocytes expressing potentially self-reactive T cell receptors (TCRs) occurs during thymocyte ontogeny. Mice deficient for CD4 expression provide a unique model system to study the contribution of the CD4 molecule in negative selection of T cells reactive against the major histocompatibility complex class II-associated retroviral self-superantigen, Mls-1a. In the presence of Mls-1a determinants, mature CD8+ T cells expressing V beta 6, 8.1, and 9 were deleted in CD4-deficient mice, thus demonstrating that TCR affinity for Mls-1a is sufficient for deletion and that a signal through CD4 was not required. However, in instances where the TCR affinity for Mls-1a is low, as in the case of V beta 7+ T cells, CD4 expression was required for clonal deletion. These results demonstrate that for Mls-1a-mediated clonal deletion of T cells, the requirement for the accessory or coreceptor function of CD4 depends on the affinity of the TCR.

Animals↗
PubMed1992

Thymic nurse cell lymphocytes react against self major histocompatibility complex.

It has been postulated that thymic nurse cells (TNC), lymphoid-epithelial complexes composed of thymocytes enclosed within major histocompatibility complex (MHC) class I+ and class II+ cortical epithelial cells, may provide an optimal microenvironment for the process of T cell selection. By transplanting single TNC in the avian chorionallantoic membrane assay we demonstrate that a significant portion of intra-TNC lymphocytes (TNC-L) possess reactivity against self-MHC molecules. The frequency of these autoreactive cells among TNC-L exceeds by far that of thymocytes or peripheral blood lymphocytes of the same donor. These results indicate that TNC-L constitute a T cell population enriched for self-MHC reactivity, i.e. cells that have undergone positive selection, but not yet deletion and/or deactivation.

Animals↗
PubMed1991

Developmental expression of IL-2-receptor light chain (CD25) in the chicken embryo.

Thymocyte differentiation obeys the same fundamental principles in mammals as in avian species. This parallelism does not only affect the developmentally controlled acquisition of CD3, 4, 8, and TcR isotype expression, but also concerns CD25, the light chain of the interleukin-2 receptor (IL-2R). On chicken thymocytes, surface CD25, which is recognized by the monoclonal antibody INN Ch16, is first observed during day 11 of embryonic life, and peaks at day 14, when it is expressed by about one-third of all lymphoid cells. CD25 is found on subsets of all thymocyte populations as defined by TcR alpha beta, TcR gamma delta, 2, CD4, and CD8 expression, cortical or medullary localization, and is also present on a subset of intrathymic nurse-cell lymphocytes. These findings suggest phylogenetic conservation of the IL-2/IL-2R-triggered differentiation pathway previously described for mammalian species, thus underlining its probable functional importance.

Animals↗
PubMed1991

[Phenotypic and functional analysis of thymic nurse cell (TNC)-lymphocytes].

Thymic nurse cells (TNC) are epithelial cells containing intact T-cells engulfed within membrane-lined vacuoles in their cytoplasm. Since thymic epithelial cells strongly express MHC class I and II antigens, these lymphoid-epithelial complexes have been considered to provide an optimal micro-environment for the process of self-recognition and/or clonal deactivation of thymocytes. The present experiments were designed to further analyze the phenotypical stage of differentiation and the functional properties of intra-TNC lymphocytes (TNC-L) at a single cell level using the chorionallantoic membrane (CAM) assay, which can only be performed in avian species and, thus, presents a unique possibility to circumvent technical problems for the functional study of TNC-L in mammals. In immunofluorescence analyses with monoclonal antibodies (mAb) to the chicken alpha/beta and gamma/delta T cell receptors (TCR) and the CD3, CD4, and CD8 equivalents, an enrichment was found of CD3+/CD4+/CD8-, CD3+/CD4-/CD8+, TCR alpha/beta + and TCR gamma/delta + cells inside TNC, as compared with extra-TNC thymocytes. Assessing micromanipulated, single chicken TNC in the CAM assay, we also demonstrated at a clonal level that TNC-L possess a strong graft-versus-host (GvH) reactivity in allogeneic combinations. This reaction showed morphological, phenotypical and functional characteristics of a classical graft-versus-host reaction (GvHR). The efficiency to induce a GvHR was higher for TNC-L than peripheral blood lymphocytes (PBL) or thymocytes from the same donor. Surprisingly, in syngeneic combinations TNC-L also react against self-MHC molecules with high frequency. The frequency in syngeneic combinations is, however, lower than in allogeneic combinations.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Intrathymic nurse cell lymphocytes can induce a specific graft-versus-host reaction.

Single chicken thymic nurse cells (TNC) placed onto the chorionallantoic membrane (CAM), showed that intra-TNC lymphocytes (TNC-L) possess a strong graft-versus-host reactivity (GVHR) in allogeneic MHC combinations. This reaction shows the morphological, phenotypic, and functional characteristics of a classical GVH reaction (GVHR). The induction of a GVHR was significantly higher for TNC-L as compared with thymocytes or peripheral blood lymphocytes (PBL). The specificity of the GVHR was shown by serial transfer experiments onto appropriate allogeneic and syngeneic secondary embryonic hosts. In immunofluorescence analyses with monoclonal antibodies (mAb) to the chicken alpha/beta and gamma/delta T cell receptors (TCR) and the CD3, CD4, and CD8 equivalents, an enrichment of CD3+/CD4+/CD8- and CD3+/CD-4-/CD8+, TCR-alpha/beta + and TCR- gamma/delta + cells was observed inside TNC as compared with extra-TNC thymocytes. A large proportion of CD4+ and/or CD8+ TCR- gamma/delta + cells were demonstrated inside TNC. A minor population among TCR- gamma/delta extra-TNC thymocytes also expressed CD4 and/or CD8 molecules. Based on functional tests and double staining experiments, we propose that CD4+/CD8+ thymocytes enter the TNC where they may undergo positive selection for MHC restriction and further differentiation to CD4 or CD8 single-positive cells. Taken together these data support the concept that TNC contribute a specialized thymic microenvironment for T cell differentiation and maturation.

Allantois↗
PubMed1989

Intra-thymic nurse cell lymphocytes can induce a graft-versus-host reaction with high efficiency.

Thymic nurse cells (TNC) are multicellular complexes composed of morphologically intact thymocytes internalized within epithelial cells. Due to their unusual features, they have been suspected to provide an appropriate microenvironment for T-cell repertoire acquisition. In recent functional studies in the chicken system, we have shown that intra-thymic nurse cell-lymphocytes (TNC-L) are highly efficient inducers of a graft-versus-host reaction (GvHR) in an allogeneic chorionallantoic membrane (CAM) assay, manifested by the formation of visible colonies, so-called pocks. Immunohistochemical and electron microscopical assessment of pocks revealed no differences between the cellular components and ultrastructural features of GvHR induced by TNC-L or peripheral blood lymphocytes (PBL). In addition, the stimulation of this local GvHR by interleukin 2 (IL-2) was demonstrated.

Animals↗
PubMedDate not supplied

Chicken thymic nurse cells: an overview.

Thymic nurse cells are multicellular complexes located in the subcortical area of the thymus of all avian, mammalian and amphibian species investigated so far. Since their first description in 1980 many studies have been carried out to characterize their morphological and functional properties. The purpose of this review is to summarize recent morphological as well a functional analyses of chicken thymic nurse cells which suggest a role of these cell complexes in T cell selection.

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