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The main scientific objectives of the Lymphocyte Population Biology Unite are:
1- To study the mechanisms that control the numbers of B and T lymphocytes – lymphocyte homeostasis – and their in preventing autoimmune diseases.
2- To study the mechanism of secondary immune responses – immunological memory.
In 2011 we have developed the following independent research projects:
1. Homeostasis of the number of activated Ig-secreting B cells
Maintenance of plasma IgM levels is critical for immune system function and homeostasis in humans and mice. However, the mechanisms that control homeostasis of the activated IgM-secreting B cells are unknown. We have reported that, in contrast to T lymphocytes that undergo considerable homeostatic proliferation, B lymphocytes expand poorly after transfer into B cell deficient mice, but fully reconstitute the pool of natural IgM-secreting B cells and circulating IgM levels. By using sequential cell transfers and B cell populations from several mutant mice, we were able to identify novel mechanisms regulating the size of the IgM-secreting B cell pool. Contrary to the previous mechanisms described regulating homeostasis, which involve competition for the same niche by cells sharing overlapping survival signals, homeostasis of the innate IgM-secreting B cell pool is also achieved when B cell populations are able to monitor the number of activated B cells by detecting their secreted products. Notably, B cell populations are able to assess the density of their activated cells by sensing their secreted IgG via FcgRIIB, a low affinity IgG receptor that is expressed on B cells and acts as a negative regulator of B cell activation by a ship-mediated pathway. The engagement of this inhibitory pathway keeps the number of activated IgM-secreting B cells under control. In conclusion, we show that the homeostasis of activated IgM-secreting B cells is maintained by a mechanism that is reminiscent of the primordial “quorum-sensing” systems previously described in bacteria, but never before been observed in a complex mammalian system. Notably, some species of bacteria modulate their growth rate according to their density by detecting some of their secreted products, a mechanism referred to as “quorum-sensing”. We hypothesize that a malfunction of this “quorum-sensing” mechanism may lead to uncontrolled B cell activation and autoimmunity.
2. The homeostasis of the IL-2 producing T cells The immune system is regulated by complex interactions between different cells subsets which are still not fully understood. We have previously shown that the n
umber of CD4+CD25+FOXP3+ regulatory CD4 T cells (Treg) is strictly controlled and directly related to the number of cells capable of producing IL-2. These findings indicate that a quorum-sensing feedback loop, where the IL-2 produced by T cell sub-population is detected by a sub-population of CD4 Treg cells expressing the high-affinity IL-2Rα-chain that controls the number of total CD4 T cells. That is to say : overall CD4 T cell populations adapt their behaviour according to the detection of the quantities of IL-2 produced. We propose to study the interactions between these two cell populations. For this purpose, we propose to :
a. study the homeostasis of the IL-2p cells in the steady-state and during homeostatic restoration by performing peripheral transfers and constructing bone marrow chimeras
b. correlate the numbers of IL-2p and Treg cells during homeostatic restoration and immune responses in existing and new mutant mouse models
We are currently investigating the homeostasis of the IL-2 producing (IL-2p) T cells, by using reporter mice expressing GFP under the control of promoter regions of IL-2. By reconstituting irradiated Rag2-/- IL-2-/- hosts with mixes of IL-2/GFP and IL-2-deficient BM cells mixed at different ratios, we found the number of IL-2p GFP+ cells recovered in the different chimeras was constant and independent of the proportion of IL-2/GFP precursors cells present in the initial inoculum, suggesting that the IL-2p cell population is under strict homeostatic control and occupies a specific niche of the peripheral T cell pools. We have also studied correlations between the total number of CD4 T cell, the number of IL-2p cells and the number of FoxP3+ Treg cells following the kinetics of reconstitution of T cell deficient mice after transfer of mature CD4+ T cell populations. We will establish whether in the course of an immune response the same correlations are also present between the different CD4 subsets.
3. Generation of homogeneous populations of monoclonal memory B cells
We propose to compare the properties of homogeneous populations of naïve and memory B cells of known antigen specificity, belonging to the same clone. So far these studies have not been possible due to our inability to generate relatively high numbers of memory B cells with known antigen specificity. In current BCR Tg mice, transgene insertion occurs randomly and does not permit Ig class switch and the generation of “bona-fide” memory B cells. To circumvent this problem we will use SWHEL mice where B cells, bearing an high-affinity BCR specific for HEL, are capable of class switch recombination and somatic hypermutation (SHM). To identify “memory B cells”, SWHEL mice will be crossed with mice where AID transcription affects the permanent expression of a YFP reporter in post-germinal center and terminally differentiated lymphocytes. These mice will be in a Rag-deficient background where only a pure population of HEL-specific B cells will be present. We will produce SWHELAID/YFP.Rag-/- mice bearing either Ly5a or the Ly5b allotype markers. B cells from these mice represent unique monoclonal populations of HEL-specific naïve cells. To generate homogeneous populations of HEL-specific memory B cells, Rag-deficient hosts were co-transferred with naïve B cells from SWHELAID/YFP.Rag-/- mice and CD4 T cells from OT-II mice, and were immunized with OVA-HEL within 24 hours of cell transfer. Using this protocol we were able to obtain anti-HEL IgG responses and homogeneous populations of memory B cells. Next, we will characterize the biological properties of these cells.
4. Establishment of new HLA-humanized mice (Resp: S. Garcia)
The use of immunocompromisedRAG-/- or SCID) mice deficient for the γ chain of IL-2R (γ-/-) and thus deprived of NK cells represented an important progress in the creation of human/mouse chimeras to study human immune cell functions in vivo. Although immune reconstitution of the γc-/- hosts by human hematopoietic progenitors was observed, many caveats impair these chimera: the number of human T cells recovered was overall poor, T cell responses are weak and restricted to by murine MHC and isotype switch of specific human antibody B cell response quasi inexistent with a predominance of human IgM secretion. We decided to improve the existing models by the means: by modulating host macrophage response and by humanizing the immune response through the expression of HLA molecules in H-2 deficient murine hosts. The reconstitution by human hematopopietic progenitors of these new hosts should provide useful animal models to study human immune responses against human pathogens such as HIV, HBV or DENGUE virus, and to test new vaccines.
Keywords: B and T cell homeostasis / immunological memory / regulatory T cells