|Lymphocyte Population Biology - CNRS URA 1961|
|HEAD||Pr FREITAS, Antonio / firstname.lastname@example.org|
|MEMBERS||DRAPIER Anne-Marie / Dr GARCIA Sylvie / LEITAO Catarina / MAILHE Marie-Pierre / MONTAUDOUIN Caroline / Dr RUEFF-JUY Dominique / SERRA Malika / THIRIOT Aude / VOUGNY Marie-Christine / ZARAGOZA Bruno
The main scientific objectives of the Lymphocyte Population Biology Unit are:
To investigate these different issues we have followed several lines of research. We summarize our most important observations during 2006:
1- Endogenous TCR recombination in TCR transgenic Rag-2 deficient mice. 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-/-γc-/- 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.
2- TCR specificity and clonal competition. We asked to which extend TCR specificity determines clonal competition for proliferation and/or survival during 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.
3- Bystander CD4+ T cell help to CD8+ T cells during lymphopenia driven proliferation (LDP). 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.
Keywords: lymphocyte homeostasis / immunological memory / regulatory T cells
Gaudin, E., Hao, Y., Rosado, M.M., Chaby, R., Girard, R. & Freitas, A.A. (2004) Positive selection of B cells expressing low densities of self-reactive BCRs. J. Exp. Med. 199 : 843-853
Sanchez-Guajardo, V., Borghans, J.A.M., Marquez, M.-E., Garcia, S. & Freitas, A.A. (2005) Different competitive capacities of Stat4- and Stat6-deficient CD4+T cells during lymphopenia-driven proliferation. J. Immunol. 174 : 1178-1187
De La Coste, A., Six, E., Fazilleau, N., Mascarell L., Legrand, N., Mailhe, M.-P., Cumano, A., Laabi, Y. & Freitas, A.A. (2005) In vivoand in absence of a thymus the enforced expression of the Notch ligands Delta-1 or Delta-4 promotes T cell development with specific unique effects. J. Immunol.174 : 2730-2737
Almeida ARM, Zaragoza B. & Freitas AA. (2006) Indexation as a novel mechanism of lymphocyte homeostasis: the number of CD4+CD25+regulatory T cells is indexed to the number of IL-2 producing cells. J. Immunol. 177 : 192-200
Hao Y., Legrand L. & Freitas AA. (2006) The clone size of peripheral CD8 T cells is regulated by TCR promiscuity. J. Exp. Med. 203 : 1643-1649
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Activity Reports 2007 - Institut Pasteur
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