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The main scientific objectives of the Lymphocyte Population Biology Unit are:
To study the mechanisms of homeostasis, which control the number of B and T lymphocytes.
To study the dynamics of the lymphocyte populations: rates of cell production and cell death, mechanisms of lymphocyte survival.
To study to what extent can cellular competition contribute to lymphocyte selection and to the control of immune responses.
To study which mechanisms induce persistence of immunological memory.
To characterize a novel B cell population present in the whole genus Mus
To investigate these different issues we have followed several lines of research. We summarize our most important observations during 2006:
Agonist driven development of CD4+CD25+Foxp3+ regulatory T cells requires a second signal mediated by Stat6. (V. Sanchez-Guajardo, S. Garcia & A. Freitas) The factors that induce Foxp3 expression and Treg cell development remain unknown. We studied the role of Stat4 and Stat6 in agonist-driven generation of antigen-specific Foxp3-expressing Treg cells. Our findings indicate that fully efficient induction of Foxp3 expression and development of antigen-specific Treg cells requires the synergistic action of two signals: a TCR-mediated signal and a second signal mediated by Stat6. Indeed, by comparing the development of wild-type, Stat4- and Stat6-deficient HA-specific T cells in the presence of HA-antigen, we found that the absence of Stat6 impaired the generation of antigen-specific CD4+CD25+Foxp3+ cells. Moreover, in transgenic mice expressing a constitutively active form of Stat6, we found that the fraction of CD4+Foxp3+ cells largely exceeds that of control wild-type littermates. Overall these findings support a role for the Stat6 pathway in Treg cell physiology.
Endogenous TCR recombination in TCR transgenic Rag-2 deficient mice (C. Montaudouin, S. Garcia & A. Freitas)
The transfer of monoclonal TCR Tg T cells from H2k 5CC7 Rag-2-/- mice, which are specific for the pigeon cytochrome C, into allogenic H2b Rag-/-gc-/- hosts resulted in the accumulation in the host mice of donor T cells expressing non-Tg TCRs. Molecular analysis of the expressed TCRs by Immunoscope confirmed that these donor T cells expressed a broad diversity of recombined endogenous TCRs. Nucleotide sequence analysis of the expressed non-Tg TCR indicates that we are in presence of a mechanism of “classical” Rag-dependent recombination in spite of the Rag-2 deficiency of the 5CC7 donors. We found that T cells expressing a non-transgenic TCR pre-exist in a very limited number both in the thymus and at the periphery of the naive 5CC7 Rag-2-/- mice. These results have important implications for the studies using TCR Rag-/- transgenic mice.
TCR specificity and clonal competition(C. Leitao, A. Freitas & S. Garcia)
The involvement of TCR/MHC-peptide interactions in the survival of CD4 and CD8 naïve T cells has been well documented. It has been proposed lymphopenia driven proliferation (LDP) is also controlled by TCR/MHC-peptide interactions. In both cases, these interactions would be of weak affinity and similar of those involved during thymic positive selection. Nevertheless, the nature of these interactions and the overlapping between those involved in the survival vs. LDP of T cells is unknown.
We asked to which extend TCR specificity determines clonal competition for survival and/or lymphopenia driven proliferation (LDP). We found that resident monoclonal T cells in TCR Tg Rag-/- mice, or monoclonal LDP derived TCR Tg T cells in Rag-/- hosts, inhibit the survival and/or the proliferation of T cells presenting the same TCR, but not of TCR Tg T cells bearing a different specificity. Using different transfer approaches we extended this notion to polyclonal T cells. Our findings show that T TCR-specificity determines peripheral T cell fate and indicate that specific sp-MHC complexes are limiting resources shared between developing, surviving and proliferating T cells.
Bystander CD4+ T cell help to CD8+ T cells during lymphopenia driven proliferation (LDP) (B. Zaragoza & A. Freitas) Since a fully functioning immune system requires a variety of lymphocyte sub-sets, lymphpocyte homeostasis should control both absolute numbers and relative sizes of each sub-population; otherwise, deregulation and disease may occur. We studied CD8:CD4 T cell interactions during LDP. We found that the co-transfer of CD8+ T cells sub-sets with naïve CD4+ cells results in the 10-fold increase of the number of CD8+ T cells recovered irrespectively of the CD8 T cell sub-set transferred. This “bystander helper” effect results in the preferential accumulation of cells with a TEM phenotype. The mechanisms that mediate the CD4 bystander helper effect are currently under investigation.
The Bw cells, a novel B cell population conserved in the whole genus Mus (A. Thiriot & D. Rueff-Juy)
Studying 9 inbred and 39 outbred wild-derived mouse strains as well as 7 laboratory mouse strains we found that the CD5+ Mac-1+ peritoneal B cell population is only present in Mus musculus domesticus subspecies. In contrast, a novel B cell population Bw is present in the whole genus Mus. We showed that this population is not restricted to the peritoneal cavity but is also present in spleen, lymph nodes and peripheral blood lymphocytes. This Bw population shares some features with but is distinct from the B-1 and B-2 populations. It is enriched in autoantibody specificities and in anti-PC antibodies but produces only low concentrations of IL-10 in contrast to B-1 cells. This population may play a key role in innate immunity.
Keywords: B cells / T cells / lymphocyte homeostasis / lymphocyte survival / immunological memory