|Lymphocyte Population Biology - CNRS URA 1961|
|HEAD||Pr FREITAS, Antonio / email@example.com|
|MEMBERS||AMADO Ines / Dr Jean-Hervé COLLE / DRAPIER Anne-Marie / Dr FERNANDEZ Tahia / Dr GARCIA Sylvie / LEITAO Catarina / MAILHE Marie-Pierre / MONTAUDOUIN Caroline / Dr MORDELET Elodie / 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 during 2008:
1- 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 require close vicinity between the interacting CD4 and CD8 T cells.
2. Selection and control of IgM-secreting cells. We studied the fate of mature lymph node (LN) B cells injected into immune-deficient hosts unable to produce B cells. Using this experimental model we found that there are mechanisms of feedback regulation controlling the total number of activated B cells and B cell terminal differentiation. We have found that the IgG produced by the first B cell population controls the production of IgM by the second B cell population. Our findings suggest that the number of activated IgM-secreting B cells may be controlled by quorum-sensing mechanisms: when Ig levels reach a certain threshold, these “signals” are captured by receptors at the B cell surface that inhibit new B cell activation.
3- Endogenous TCR recombination in TCR transgenic Rag-2 deficient mice. The transfer of monoclonal TCR Tg T cells from Rag-2-/- mice, into allogenic Rag-/-γc-/- hosts results in the accumulation in the host mice of donor T cells expressing non-Tg TCRs. Molecular analysis of the expressed TCRs confirmed that these donor T cells expressed a broad diversity of recombined endogenous TCRs. Nucleotide sequence analysis indicates that we are in presence of a “classical” Rag-dependent recombination in spite of the Rag-deficiency of the donors. We found that the T cells expressing non-transgenic TCRs pre-exist in a very limited number both in the thymus and at the periphery of the donor Rag-2-/- mice.
Keywords: lymphocyte homeostasis, immunological memory, regulatory T cells
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
Sanchez-Guajardo, V., Tanchot, C., O’Malley, J.T., Kaplan, M.H., Garcia, S. & Freitas, A.A. (2007) Agonist-driven development of CD4+CD25+Foxp3+regulatory T cells requires a second signal mediated by Stat6. J. Immunol. 178 : 7550-7556
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