Murine Superficial Lymph Node Surgery

In the field of immunology, to understand the progression of an immune response against a vaccine, an infection or a tumour, the response is often ...

Maisonneuve-Rosemont Hospital Research Center

University of Montreal

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.

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

Clonal selection of T cells occurs in the thymus and is responsible for generating a useful and functional repertoire of T cells. Aberrations in clonal selection result in altered T-cell homeostasis in the secondary lymphoid organs ranging from an absence of T cells to an overabundance of autoreactive T cells. The advent of new technologies facilitating the manipulation of the mouse genome has helped refine our understanding of the molecular and genetic pathways involved in clonal selection and has also revealed a high degree of complexity. Herein, we attempt to review recent advances in thymic selection processes, achieved mostly through genetic manipulations.

Molecular and genetic parameters defining T-cell clonal selection.

Innate CD8 T cells are found in mutant mouse models, but whether they are produced in a normal thymus remains controversial. Using the RAG2p-GFP mouse model, we found that ∼10% of TCRαβ(+) CD4(-)CD8(+) thymocytes were innate polyclonal T cells (GFP(+)CD44(hi)). Relative to conventional T cells, innate CD8 thymocytes displayed increased cell surface amounts of B7-H1, CD2, CD5, CD38, IL-2Rβ, and IL-4Rα and downmodulation of TCRβ. Moreover, they overexpressed several transcripts, including T-bet, Id3, Klf2, and, most of all, Eomes. Innate CD8 thymocytes were positively selected, mainly by nonhematopoietic MHCIa(+) cells. They rapidly produced high levels of IFN-γ upon stimulation and readily proliferated in response to IL-2 and IL-4. Furthermore, low numbers of innate CD8 thymocytes were sufficient to help conventional CD8 T cells expand and secrete cytokine following Ag recognition. This helper effect depended on CD44-mediated interactions between innate and conventional CD8 T cells. We concluded that innate TCRαβ(+) CD8 T cells represent a sizeable proportion of normal thymocytes whose development and function differ in many ways from those of conventional CD8 T cells.

Article	Year
Journal of leukocyte biology\| PubMed ID: 17554014	2007
Journal of immunology (Baltimore, Md. : 1950)\| PubMed ID: 12097370	2002
EMBO reports\| PubMed ID: 12151334	2002
Blood\| PubMed ID: 12393700	2003
Blood\| PubMed ID: 12702501	2003
An essential function of the mitogen-activated protein kinase Erk2 in mouse trophoblast development. EMBO reports\| PubMed ID: 14502223	2003
Journal of immunology (Baltimore, Md. : 1950)\| PubMed ID: 15494489	2004
Biomaterials\| PubMed ID: 15664639	2005
Journal of immunology (Baltimore, Md. : 1950)\| PubMed ID: 16177081	2005
European journal of immunology\| PubMed ID: 17918202	2007
Proceedings of the National Academy of Sciences of the United States of America\| PubMed ID: 19074272	2008
Immunology and cell biology\| PubMed ID: 20585337	2011
Molecular and genetic parameters defining T-cell clonal selection. Immunology and cell biology\| PubMed ID: 20956988	2011
PloS one\| PubMed ID: 21060788	2010
Development and function of innate polyclonal TCRalphabeta+ CD8+ thymocytes. Journal of immunology (Baltimore, Md. : 1950)\| PubMed ID: 21844388	2011
Journal of immunology (Baltimore, Md. : 1950)\| PubMed ID: 22075697	2011
PloS one\| PubMed ID: 22291907	2012

Nathalie Labrecque

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