The impact of the cytoskeleton dynamics on immune responses

摘要: Immune cells are susceptible to a variety of external stimuli that triggers cell surface receptors, leading activation intracellular proteins and changes in the actin cytoskeleton. The Rho-GTPases family regulate several aspects polymerization. They take part an intricate network other can therefore have direct or indirect role functions. In this study I aimed define Cdc42 Rac2, as well effector WASp N-WASp adaptive immune system. paper aim was dissect particular contribution WASp-deficiency induction skin pathology Wiskott-Aldrich syndrome patients, using mouse models. Our showed WASp-deficient dendritic accumulate skin; were able induce increase cross-presentation exogenous antigen increased CD8 T proliferation vivo vitro. This caused by expression Rac2 cytoplasm, which regulates phagosomal pH promotes loading on MHC class molecules. II we understand for B where deleted conditionally mature cells. Mice with Cdc42-deficient reduced marginal zone follicular numbers. Immunized mice had germinal center associated specific antibody titers serum. vitro assays revealed less spreading antibody-coated surfaces skewed CD4 towards more production IFN IL-2. III studied combined deficiency A KO only (cDKO) used. Compared WT mice, cDKO large reduction decreased precursors also failed mount response both Tdependent T-independent antigens titers, together uptake transportation follicle. IV investigated effect hyperactive mutated WASp, found X-linked neutropenia murine XLN-WASp mutations induced polymerized We detected but normal chemotaxis toward chemokines types. observed not apoptosis types latter is probably due genomic instability FISH-telomere assay. Altogether, shows Rho GTPases their crucial correct function cellular humoral responses. Notably, phenotypic severity be depletion closely related suggesting existence compensatory mechanisms overlapping roles. characterization may contribute precise interventions therapeutic success. LIST OF SCIENTIFIC PAPERS I. Baptista M.A.P., Keszei M., Sunahara K., Dahlberg C., Lieden A., Kuo I.-C., Wallin R.P.A, Snapper S.B., Eidsmo L., Scheynius Karlsson M.C.I., Bouma G., Burns S.O., Forsell M.N., Thrasher A.J., Nylen S., Westerberg L.S. Deletion protein activity Submitted II. Gerasimcik N., C.I., Ramesh Geha R.S., L.S., Severinson E. devoid GTPase severely deficient dependent signaling III. Moran C.J., Detre Eston M.A., Alt F.W., Terhorst Notarangelo L.D., S.B. (WASP) N-WASP critical peripheral B-cell development Blood 2012 March, 119(17):3966-74 IV. Meelu P., Adamovich D.A., Cottade-Almeida V., Seed B., Rosen M.K., Vandenberghe Klein Activating WASP result enhanced polymerization, altered cytoskeletal responses, lymphocytes J. Exp. Med. 2010 May, 207(6):1145-52