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Biomedical subjects

S Viville

Publications and source records attributed to S Viville.

12 recordsLinked to original sources
PubMed1996

Antiviral immune responses of mice lacking MHC class II or its associated invariant chain.

Induction of T-helper cells and T-B cell interaction have been considered to critically depend upon recognition of major histocompatibility complex (MHC) class II molecules by the T cell receptor. Mice lacking either MHC class II molecules (class II(0/0) mice) or its associated invariant chain (Ii0/0 mice) provide new opportunities to test this premise. Immune responses to some protein antigens have been studied in these mice; little is known about their ability to withstand viral infections. We therefore tested CD8+ effector T cells and CD4+ T-cell-dependent B cell function during different viral infections. The vesicular stomatitis virus (VSV)-specific primary cytotoxic T cell response which is largely T-helper-dependent was diminished in Ii(0/0) and absent in class II(0/0) mice. The usually less T-helper-dependent cytotoxic vaccinia or lymphocytic choriomeningitis virus (LCMV)-specific CD8+ T cell responses were reduced up to ninefold in class II(0/0) and up to threefold in Ii(0/0) mice. In class II(0/0) mice, the T-helper-independent neutralizing IgM response against the glycoprotein of VSV was within normal ranges but, in contrast to previous results on CD4(0/0) mice, the T-helper-dependent IgG response was absent. Ii(0/0) mice exhibited a normal neutralizing IgM response; in contrast to class II(0/0) mice, they mounted a significant, though reduced specific IgG response. Similar results were obtained for antibody responses against the nucleoprotein of VSV. Although the T-helper-cell response upon infection with VSV seemed diminished only a little in Ii(0/0) mice, presentation of VSV-G to a class II-restricted specific hybridoma was greater than 300-fold reduced in the absence of Ii. This suggests that local protein concentrations reached during viral infection in the host are high enough to override the Ii deficiency of antigen-presenting cells in vivo.

Animals↗
PubMed1995

Towards unravelling the Igf2/H19 imprinted domain.

Genomic imprinting is an epigenetic marking process that confers parent-of-origin-dependent expression on certain genes. These imprinted genes are sometimes found in clusters, suggesting a possible involvement of higher order regulatory elements controlling expression and imprinting of genes organised in such clusters. In the distal chromosome 7 there are at least four imprinted genes: Mash2, Ins2, Igf2 and H19. Recent evidence suggests that imprinting and expression of at least Igf2 and H19 may be mechanistically linked.

Animals↗
PubMed1995

The influence of invariant chain on the positive selection of single T cell receptor specificities.

The appearance of peptide-loaded major histocompatibility complex (MHC) class II molecules at the cell surface depends critically on the invariant chain (Ii). We have studied the influence of Ii on the positive selection of CD4+ T cells, mediated by class II molecules expressed on thymic stromal cells. Invariant chain-deficient mice (Iio) were crossed with different T cell receptor (TcR) transgenic strains and the emergence of mature CD4 single-positive thymocytes measured in Iio/TcR transgenic offspring. Positive selection was nearly absent in Iio/2B4 mice, which display receptors specific for a moth cytochrome c (MCC) peptide in the context of Ek. In addition, no T cell response was elicited when nontransgenic Iio animals were injected with this peptide, even though antigen-presenting cells (APC) from such mice were perfectly capable of presenting it, suggesting that selection of the entire anti-MCC 88-103 repertoire depends on Ii. Positive selection also appeared strongly reduced in another line of Iio/TcR transgenic mice (Iio/BDC2.5). However, in sharp contrast, a third line (Iio/3A9) exhibited almost normal positive selection of thymocytes displaying the transgene-encoded receptor. These thymocytes were exported to the periphery: peripheral T cells could respond normally to the appropriate peptide in vitro. The most likely interpretation of these findings is that selection of most CD4+ T cells depends on MHC class II complexes loaded with peptide in an Ii-dependent pathway, but some can be selected on class II complexes that are either loaded along an alternative, Ii-independent, route or are empty. This is consistent with the involvement of peptide in positive selection of CD4+ T cells, for which there exists little prior evidence.

Animals↗
PubMed1995

Peg1/Mest imprinted gene on chromosome 6 identified by cDNA subtraction hybridization.

Parthenogenesis in the mouse is embryonic lethal partly because of imprinted genes that are expressed only from the paternal genome. In a systematic screen using subtraction hybridization between cDNAs from normal and parthenogenetic embryos, we initially identified two apparently novel imprinted genes, Peg1 and Peg3. Peg1 (paternally expressed gene 1) or Mest, the first imprinted gene found on the mouse chromosome 6, may contribute to the lethality of parthenogenones and of embryos with a maternal duplication for the proximal chromosome 6. Peg1/Mest is widely expressed in mesodermal tissues and belongs to the alpha/beta hydrolase fold family. A similar approach with androgenones can be used to identify imprinted genes that are expressed from the maternal genome only.

Amino Acid Sequence↗
PubMed1995

Protective effect of low doses of an anti-IL-4 monoclonal antibody in a murine model of acute toxoplasmosis.

Treatment with an anti-IL-4 monoclonal antibody protected susceptible C57BL/6 mice against challenge with an avirulent strain of T. gondii. Antibody therapy with 100 micrograms on days 0 and 7 post infection resulted in 100% survival of C57/BL6 mice infected orally. Survival was dose-dependent. Treatment prolonged parasitaemia but did not alter tissue parasite load. Increased serum IgG2a and IFN-gamma levels, together with low levels of IgG1, in mice treated with anti-IL-4 or an isotype control, indicated a trend towards a predominant Th1 response in all survivors. The persistence of an IgE response after treatment suggests that endogenous IL-4 was only partly neutralized or that other factors can induce the production of IgE in murine toxoplasmosis.

Acute Disease↗
PubMed1994

Diversity of endogenous epitopes bound to MHC class II molecules limited by invariant chain.

The invariant chain (Ii) binds nascent major histocompatibility complex (MHC) class II molecules, blocking peptide binding until the complex dissociates in the endosomes. This may serve to differentiate the MHC class I and II antigen presentation pathways and enable class II molecules to efficiently bind peptides in the endosomes. This hypothesis was addressed by probing spleen cells from a combination of knock-out and transgenic mice with a large panel of T cell hybridomas. The Ii molecule blocked the presentation of a range of endogenously synthesized epitopes, but some epitopes actually required Ii. Thus, the influence of Ii on presentation does not follow simple rules. In addition, mice expressing Ii were not tolerant to epitopes unmasked in its absence, a finding with possible implications for autoimmunity.

Amino Acid Sequence↗
PubMed1993

Mice lacking the MHC class II-associated invariant chain.

The invariant chain (li) has aroused much interest because of its close association with major histocompatibility complex (MHC) class II molecules. Various functions have been proposed for it; several of these have received experimental support, but most have not been definitively proven, owing largely to uncertainties inherent in the experimental systems employed. We have now generated a line of mice devoid of the invariant chain by introducing a drastic mutation into the li gene. Cells from mutant animals show aberrant transport of MHC class II molecules, resulting in reduced levels of class II complexes at the surface, and these do not have the typical compact conformation indicative of tight peptide binding. Consequently, mutant cells present protein antigens very poorly and mutant mice are deficient in producing and at negatively selecting CD4+ T cells.

Animals↗
PubMed1991

The E alpha promoter: a linker-scanning analysis.

To accurately delineate the DNA sequence elements involved in the transcriptional regulation of the murine MHC class II gene E alpha, we have constructed a set of "linker-scanning" mutants of the E alpha promoter region. These were made by the gapped heteroduplex technique and result in a set of 10-bp replacement mutations, covering the -206 to -6 stretch of the promoter. The effect of these mutations on transcriptional activity was evaluated in several systems, either by transfection into cultured cells or by in vitro transcription. The data points to the now classical X and Y boxes as the most important control elements, either for constitutive expression in B lymphoma cells, or for IFN-gamma-inducible expression in macrophages. Motifs upstream of the X box also play a role, but are somewhat less critical. Overall, we find no marked difference between regulatory strategies in B lymphomas or activated macrophages.

Animals↗
PubMed1989

Fine-tuning of MHC class II gene expression in defined microenvironments.

Strict control of major histocompatibility complex class II gene expression is essential for proper functioning of the immune system. Recent transgenic mouse studies have revealed an intricate fine-tuning of class II gene transcription in microenvironments such as the germinal centers and thymic cortex and medulla.

Animals↗