organisation - the Instituto Gulbenkian de Ciência

LYMPHOCYTE
PHYSIOLOGY
Jocelyne Demengeot Principal Investigator
PhD in Cellular and Molecular Biology, Université AIX-MARSEILLE II, 1989
Post-doctoral Fellow, Columbia University, NY, USA
HHMI Research Associate - Harvard Medical School, Boston, USA
Research Associate, Institut Pasteur, Paris, France
Deputy Director for Scientific Affairs
Scientific supervisor of the Antibody production facility
Head of the Animal House facility
Principal Investigator at the IGC since 1998
We are concerned with those properties of the immune system that guarantee
tissue integrity as well as tolerance to commensals and food antigens while
maintaining the ability to mount efficient responses to infectious agents. We
approach the cellular and molecular bases of immune regulation through the
analysis of various mouse models, notably of spontaneous or induced autoimmune
and immuno-pathological inflammation. Keeping in mind that the vertebrate
immune system relies on the production of a very large diversity of
antigen receptors through genomic rearrangement by the RAG recombinases,
we also maintain a line of research assessing the consequences of deregulated
RAG activity on genomic integrity and on lymphocyte homeostasis. Our
interests merge within various collaborative projects, notably addressing the
efficiency of immunotherapies for Systemic Lupus Erythematosus, Rheumatoid-
Arthritis and Type-1 Diabetes.
GROUP MEMBERS
Andreia Lino (Post-doc)
Elodie Mohr (Post-doc)
Marie Bonnet (Post-doc)
Marie Louise Bergman (Post-doc)
Ricardo Paiva (PhD student)
Sandra Gama Garcies (PhD student, left in October)
Aleksandra Gumienny (Technician, started in October)
Ana Paula Regalado (Technician, started in November)
Catarina Martins (Technician)
Maria Espírito Santos (Technician, left in June)
Rosa Maria Santos (Technician, left in November)
FUNDING
Fundação para a Ciência e a Tecnologia (FCT), Portugal
Framework Programme 7, European Commission
RAG MEDIATED DNA REARRANGEMENT
The adaptive immune system of the jawed vertebrates emerged about 500
million years ago involving, as a major novelty, the somatic generation of an
extremely large diversity of antigen receptors by a mechanism of site specific
DNA recombination. The Rags introduce DNA breaks at specific sequences -
named Recombination Signal Sequences (RSS) found at the border of a large set
of gene segments. RSS are composed of either 28 or 39 nucleotides, only a few
of which are conserved. Given this degeneracy, RSS-like sequences can be identified
outside the antigen receptor loci. Such “cryptic-RSS” (cRSS) have been occasionally
tested, shown to support Rag mediated recombination and involved
in the emergence of some lymphoid tumours. With the aim to formally establish
the frequency, efficiency and nature of cRSS in the genome, we joined with five
other groups at IGC to combine experimental, bio-informatic and mathematical
approaches to perform unbiased large-scale analyses.
To calibrate a novel model identifying RAG targets, we experimentally scored
60 RSS pairs using our new fluorescence based reporter of Rag activity. We also
classified epigenetic markers and defined the genetic repertoire in differentiating
lymphocytes, at the corresponding V locus. In parallel, we confirmed that our
novel transgenic mouse model, where Rag activity can be induced upon oral administration
of tamoxiphen, is amenable to test the effect of Rag activity in vivo.
IMMUNE REGULATION
A subset of T cells, expressing the transcription factor Foxp3, dampens immune
responses in an antigen specific manner. These cells are first selected in the
thymus through interaction with an MHC-peptide expressed locally and therefore
encompass a TCR repertoire enriched in self-reactivities. Yet, a wide array
of molecules produced by commensals, brought in by food or expressed by the
foetuses is also tolerated by the immune system. This paradox calls for a formal
evaluation of the rules governing Treg differentiation, their maintenance and
expansion as well as their domain of competences. Our specific aims are:
1. To establish the origin of the antigens that drive regulatory T cells;
2. To establish the origin of regulatory T cell specific to strictly peripheral
antigens;
3. Along with the hygiene theory, to test the role of the microbiota in modulating
immune tolerance;
4. To asses the role of B cells and B cell products in the control of T cell
homeostasis.
CONFOCAL MICROSCOPY IMAGES OF SPLEEN SECTIONS REVEALING A SPECIFIC
ROLE FOR SECRETED IMMUNOGLOBULIN M (IGM) IN THE CONTROL OF MARGINAL
ZONE (MZ) B CELLS NUMBER.
Arrowheads indicate the MZ B cells (IgM+, blue) at the periphery of the periarteriolar
lymphatic sheaths formed by the T zone (CD3e+, green) and the follicles
(IgM+IgD+, pink). A) wild-type mice. B) AID-/- mutant that produces IgM but no
other immunoglobulins. C) µS-/- mutant that cannot secrete IgM but produces
other immunoglobulins.
IGC ANNUAL REPORT ‘11
RESEARCH GROUPS
34