Biomedical subjects

Nathalie Labrecque

Publications and source records attributed to Nathalie Labrecque.

8 recordsLinked to original sources

PubMed2005

IL-7 receptor expression levels do not identify CD8+ memory T lymphocyte precursors following peptide immunization.

Identification of the mechanisms underlying the survival of effector T cells and their differentiation into memory T lymphocytes are critically important to understanding memory development. Because cytokines regulate proliferation, differentiation, and survival of T lymphocytes, we hypothesized that cytokine signaling dictates the fate of effector T cells. To follow cytokine receptor expression during T cell responses, we transferred murine TCR transgenic T cells into naive recipients followed by immunization with peptide emulsified in adjuvant or pulsed on dendritic cells. Our findings did not correlate IL-7R alpha-chain and IL-2R beta-chain expression on effector CD8+ cells with the generation of memory T lymphocytes. However, we could correlate the extent of IL-7R alpha expression down-regulation on effector T cells with the level of inflammation generated by the immunization. Furthermore, our findings showed that the maintenance of a high level of IL-7R expression by effector T cells at the peak of the response does not preclude their death. This suggests that maintenance of IL-7R expression is not sufficient to prevent T cell contraction. Thus, our results indicate that expression of the IL-7R is not always a good marker for identifying precursors of memory T cells among effectors and that selective expression of the IL-7R by effector T cells should not be used to predict the success of vaccination.

Adoptive Transfer↗

PubMed2005

Inflammatory response to peritoneal implantation of alginate-poly-L-lysine microcapsules.

A thorough understanding of the mechanisms involved in the host reaction to alginate-poly-L-lysine microcapsules (HRM) is important to design methods for the evaluation, selection, and development of biocompatible biomaterials and microcapsules or treatments to control this reaction. The objective of this study was to identify those immune cells and cytokines involved in the pathogenesis of the HRM. The total and differential cell counts were evaluated, and the mRNA expression of TNF-alpha, IL-1beta, IL-6 and TGF-beta1 was measured in peritoneal washings at 3, 17, 48, 96 and 168 h after saline or microcapsule injections. Neutrophil number and IL-1beta and IL-6 m-RNA expression presented an early transient increase, with no differences between saline and microcapsule injections, suggesting a reaction to the procedure. Macrophages, lymphocytes and TNF-alpha were significantly more activated over a longer period of time, after microcapsule implantation than saline injection. They are likely involved in transforming the reaction into a chronic inflammatory process. TGF-beta1 and IL-1beta presented a late (day 7) significant increase after microcapsule but not saline injections. They are likely involved in transforming the reaction into a fibrogenic process. These results suggest that macrophages, lymphocytes, TNF-alpha, IL-1beta and TGF-beta1 play a role in the pathogenesis of the HRM.

Alginates↗

PubMed2004

The selective increase in caspase-3 expression in effector but not memory T cells allows susceptibility to apoptosis.

Caspases play a central role in T lymphocyte activation and death. We have demonstrated previously that caspase-3, an effector molecule for activation-induced cell death (AICD), is processed following T cell activation in the absence of apoptosis. We report in this study that caspase-3 mRNA levels were selectively increased in peripheral T cells, following Ag receptor-mediated activation. The up-regulation of caspase-3 mRNA was confined to cells in the early phases of the cell cycle (G0/G1) and was independent of IL-2 signaling. This increase led to the renewal of procaspase-3 as evidenced by a 6-fold up-regulation of the zymogen in nonapoptotic stimulated T cells. The increase of mRNA levels and of both the zymogen and the cleaved forms of caspase-3 was observed in in vivo stimulated Ag-specific effector, but not memory T cells, correlating with the enhanced susceptibility of effector T cells to AICD. Furthermore, we confirm that caspase-3 levels directly influence the sensitivity of activated T cells to apoptosis, as shown using T lymphocytes isolated from caspase-3 heterozygous and knockout mice. These findings indicate that the selective up-regulation of caspase-3 transcription is required to maintain the cytoplasmic levels of this protease, which control AICD and T cell homeostasis.

Animals↗

PubMed2003

An essential function of the mitogen-activated protein kinase Erk2 in mouse trophoblast development.

The closely related mitogen-activated protein kinase isoforms extracellular signal-regulated kinase 1 (ERK1) and ERK2 have been implicated in the control of cell proliferation, differentiation and survival. However, the specific in vivo functions of the two ERK isoforms remain to be analysed. Here, we show that disruption of the Erk2 locus leads to embryonic lethality early in mouse development after the implantation stage. Erk2 mutant embryos fail to form the ectoplacental cone and extra-embryonic ectoderm, which give rise to mature trophoblast derivatives in the fetus. Analysis of chimeric embryos showed that Erk2 functions in a cell-autonomous manner during the development of extra-embryonic cell lineages. We also found that both Erk2 and Erk1 are widely expressed throughout early-stage embryos. The inability of Erk1 to compensate for Erk2 function suggests a specific function for Erk2 in normal trophoblast development in the mouse, probably in regulating the proliferation of polar trophectoderm cells.

Animals↗

PubMed2003

Changes in the lymph node microenvironment induced by oncostatin M.

Oncostatin M (OM) transforms the lymph node (LN) into a "super lymphoid organ" with 2 striking features: massive thymus-independent T-cell development and major expansion of the memory T-cell pool. We report that T-cell development in the LckOM LN is regulated by a cyclooxygenase-2 (COX-2)-dependent neoangiogenesis involving high endothelial venules (HEVs). That LN HEVs are particularlyrich in OM-receptor beta-chain provides aplausible explanation for the fact that extrathymic T-cell development in LckOM mice is limited to the LN. Moreover, we found that increased production of the CCL20 chemokine by LN stromal cells was instrumental in the expansion of the memory phenotype CD4 T-cell pool in LckOM mice. The generality of the latter finding was demonstrated by the fact that CCL20/CCR6 interactions increase the basal proliferation rate of CD62L(lo) CD4 T cells irrespective of their thymic (in non-OM-transgenic mice) or extrathymic (in LckOM mice) origin. To our knowledge, CCL20 is the first molecule found to increase the proliferation of memory phenotype CD4 T cells. These findings identify potential targets for the creation of thymic substitutes (LN HEVs) and for expansion of the CD4 memory T-cell compartment (CCL20).

Animals↗

PubMed2002

Tissue distribution of target antigen has a decisive influence on the outcome of adoptive cancer immunotherapy.

Adoptive transfer of allogeneic T cells has unmatched efficacy to eradicate leukemic cells. We therefore sought to evaluate in kinetic terms interactions between T cells and allogeneic leukemic cells. T cells primed against the model B6(dom1) minor histocompatibility antigen were adoptively transferred in irradiated B10 (B6(dom1)-positive) and congenic B10.H7(b) (B6(dom1)-negative) recipients, some of which were also injected with EL4 leukemia/lymphoma cells (B6(dom1)-positive). A key finding was that the tissue distribution of the target epitope dramatically influenced the outcome of adoptive cancer immunotherapy. Widespread expression of B6(dom1) in B10 recipients induced apoptosis and dysfunction of antigen-specific T cells. Furthermore, in leukemic B10 and B10.H7(b) hosts, a massive accumulation of effector/memory B6(dom1)-specific T cells was detected in the bone marrow, the main site of EL4 cell growth. The accumulation of effector/memory cells in recipient bone marrow was EL4 dependent, and its kinetics was different from that observed in recipient spleen. We conclude that strategies must be devised to prevent apoptosis of adoptively transferred T cells confronted with a high antigen load and that local monitoring of the immune response at the site of tumor growth may be mandatory for a meaningful assessment of the efficacy of adoptive immunotherapy.

Animals↗

PubMed2002

Murine spermatogonial stem cells: targeted transgene expression and purification in an active state.

A 400 bp fragment of the spermatogonia-specific Stra8 locus was sufficient to direct gene expression to the germinal stem cells in transgenic mice. A fractionation procedure was devised, based on immunomagnetic sorting of cells in which the promoter drives the expression of a surface functionally neutral protein tag. The purified cells expressed the known molecular markers of spermatogonia Rbm, cyclin A2 and EP-Cam, and the beta1- and alpha6-integrins characteristic of the stem cell fraction. A 700-fold enrichment in stem cells was determined by the ability of the purified fractions to re-establish spermatogenesis in germ cell-depleted recipient testes.

Age Factors↗

PubMed2002

Thymic and extrathymic T cell development pathways follow different rules.

Separation between primary and secondary lymphoid organs is a universal feature in jawed vertebrates. Strikingly, oncostatin M (OM)-transgenic mice present massive extrathymic T cell development, localized exclusively in the lymph nodes (LN). According to the prevailing paradigm, the thymus is the main source of T lymphocytes in gnathostomes mainly because thymic epithelial cells have a unique ability to support early steps in T cell development. It is therefore remarkable that productive T cell development occurs in the OM(+) LN, despite the absence of epithelial cells. The present study shows that in the OM(+) LN: 1) MHC class I expression strictly on hemopoietic cells is sufficient to support the development of a diversified repertoire of CD8 T cells; 2) the efficiency of positive selection of specific TCR-transgenic T cells is not the same as in the thymus; 3) negative selection is very effective, despite the lack of an organized thymic-like medulla. Furthermore, our data suggest that extrathymic T lymphocytes developing in the OM(+) LN undergo extensive postselection expansion because they live in the microenvironment in which they were positively selected. This work illustrates how the division of labor between primary and secondary lymphoid organs influences the repertoire and homeostasis of T lymphocytes.

Animals↗