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Role of Quorum Sensing mechanisms in the Immune System s regulation

Final Report Summary - QSIS (Role of Quorum Sensing mechanisms in the Immune System's regulation)

The homeostatic control of lymphocyte numbers provides the immune system with a basic mechanism that shapes the repertoire of the immune-competent cells and therefore, the capacity to respond to exogenous antigens as well as to maintain self-tolerance. Homeostatic mechanisms will also enable the re-establishment of the immune system following disruption (irradiation and/or chemotherapy). During the process of restoration, the immune system can be reset at a new equilibrium overcoming any of its previous malfunctions. This capacity of homeostatic regulation may therefore be used in potential therapeutic strategies to radically modify lymphocyte repertoires, immune responses, autoimmune disease and allergy. We found that control of lymphocyte numbers (B and T cells) can also be achieved by their ability to perceive the density of their own populations, i.e. lymphocytes use “quorum-sensing” mechanisms to coordinate their gene expression according to the density of their population.
By using sequential cell transfers and B cell populations from several mutant mice, we identified the novel mechanisms regulating the size of the IgM-secreting B cell pool. Contrary to previous mechanisms described regulating homeostasis, which involve competition for the same niche by cells having overlapping survival requirements, homeostasis of the innate IgM-secreting B cell pool is also achieved when B cells 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 activated B cells by sensing their secreted IgG. This process involves the FcγRIIB, a low-affinity IgG receptor that is expressed on B cells and acts as a negative regulator of B cell activation, and its intracellular effector the inositol phosphatase SHIP. As a result of the engagement of this inhibitory pathway the number of activated IgM-secreting B cells is kept under control.
We investigated the regulation of the size of IL-2-producing CD4+T-cell (IL-2p) pool using different IL-2-reporter mice. We found that in the absence of either IL-2 or regulatory CD4+T-cells (Treg) the number of IL-2p-cells increases. Administration of IL-2 decreases the number of cells of the IL-2p-cell-lineage and pertinently, abrogates their ability to produce IL-2 upon in vivo cognate stimulation, while boosting Treg-cell numbers. Thus, we demonstrated that homeostasis of the IL-2p-cell lineage occurs via a quorum-sensing-like mechanism, where the IL-2 produced is sensed by Treg-cells, which reciprocally regulate the cells of the IL-2p-cell-lineage. In conclusion, Interleukin-2 (IL-2) acts as a master regulator of immune homeostasis as CD4+T-cells restrain their growth by monitoring IL-2 levels thus, preventing uncontrolled responses and autoimmunity. This mechanism operates in the course of immune responses and plays a major role in the contraction phase allowing preventing excessive accumulation of aggressive cells.
We hypothesize that malfunction of this quorum-sensing mechanism may lead to uncontrolled lymphocyte activation and autoimmunity. Our findings raise important implications for the therapy of autoimmune diseases, vaccination strategies and approaches designed to exploit the adoptive transfer of memory B cells in immunotherapy.