Interaktion der Bim- und CD95-gesteuerten Apoptosewege in Lymphopoese und Immunantwort
Zusammenfassung der Projektergebnisse
Proapoptotic BH3-only proteins are essential for the programmed cell death of antigen-specific B and T cells during the shutdown of an immune response. In this project we have investigated the contribution of various BH3-only proteins in this process. T cell-dependent B-cell immune responses induce germinal centers that are sites for expansion, diversification, and selection of antigen-specific B cells. During the immune response, antigen-specific B cells are removed in a process that favors the retention of cells with improved affinity for antigen, a cell death process inhibited by excess Bcl-2. In this first study, we examined the role of the BH3-only protein Bim, an initiator of apoptosis in the Bcl-2-regulated pathway, in the programmed cell death accompanying an immune response. After immunization, Bim-deficient mice showed persistence of both memory B cells lacking affinity-enhancing mutations in their immunoglobulin genes and antibodyforming cells secreting low-affinity antibodies. This was accompanied by enhanced survival of both cell types in culture. We have identified for the first time the physiologic mechanisms for killing low-affinity antibody-expressing B cells in an immune response and have shown this to be dependent on the BH3-only protein Bim. During acute T cell immune responses to viral infection, antigen-specific T cells first proliferate and differentiate into effector cells, but after pathogen clearance most are deleted by apoptosis. The developmentally programmed death of antigen-specific T cells during shutdown of a T cell response is mediated by the Bcl-2-regulated apoptotic pathway and partly depends on the proapoptotic BH3-only protein Bim. However, loss of Bim enhanced survival of antigenactivated T cells to a lesser extent than Bcl-2 overexpression, indicating that other proapoptotic factors must contribute to T cell killing. In this second study, we investigated the contributions of several BH3-only proteins to the shutdown of an acute T cell immune response in vivo. After infection with human herpes simplex virus (HSV-1), mice lacking Noxa, Bid, or Bad had a normal increase and subsequent decline in the numbers of antigen-specific CD8+ T cells. In contrast, Puma-deficient mice showed an abnormally prolonged persistence of antigenspecific CD8+ T cells in the spleen, associated with enhanced in vitro survival of these cells in the absence of cytokines. Puma was dispensable for viral clearance and also did not play a role in proliferation or activation of HSV-1-specific CD8+ T cells in vivo. Collectively, these findings show that Puma contributes to the death of antigen-specific T cells during shutdown of an immune response.
Projektbezogene Publikationen (Auswahl)
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Pro-apoptotic BH3-only Protein Bim Is Essential for the Developmentally Programmed Death of Germinal Center-Derived Memory B Cells and Antibody Forming Cells during Shutdown of an Immune Response. Blood. 2007 Dec 1;110(12):3978-84. Epub 2007 Aug 24
Fischer SF, Bouillet P, O'Donnell K, Light A, Tarlinton DM and Strasser A
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BH3-only protein Puma contributes to death of antigen-specific T cells during shutdown of an immune response to acute viral infection. Proc Natl Acad Sci USA. 2008 Feb 26;105(8):3035-40, Epub 2008 Feb 19
Fischer SF, Beiz G and Strasser A
