title: The role of the actin-remodeling proteins L-plastin and cofilin-1 in mast cells and B cells
creator: Kramer, Johanna
subject: ddc-500
subject: 500 Natural sciences and mathematics
subject: ddc-570
subject: 570 Life sciences
description: Various processes in immune cells require regulated actin cytoskeleton remodeling which is mediated by a plethora of proteins. The functions of the actin-remodeling proteins cofilin-1 (Cfl1) and L-plastin (LPL) in B cells and mast cells have not been fully elucidated so far.  The actin-severing and -depolymerizing protein Cfl1 is ubiquitously expressed in non-muscle cells including immune cells. Functional Cfl1 is essential for αβ T cell development and T cell costimulation. One aim of this thesis was to find out whether Cfl1 expression is also required for normal B cell and mast cell organization. Mice expressing non-functional Cfl1 mast cell-specifically were devoid of connective tissue mast cells (CTMCs) and did not develop systemic anaphylaxis. Thus, they are a suitable model for CTMC deficiency. CTMC-deficient mice showed normal reactions in in vivo models for allergic contact dermatitis, psoriasis, and clearing vaccinia virus-induced skin infection demonstrating no major impact of CTMCs in these disease models. Mice with B cell-specific expression of non-functional Cfl1 had drastically diminished B cell numbers in spleen, lymph nodes, blood, and peritoneum. Also, in the bone marrow the percentage of B cells was reduced. Residual B cells were shown to have an imperfect knock-in of non-functional Cfl1. In summary, expression of non-functional Cfl1 instead of the wildtype protein specifically in B cells or mast cells revealed a fundamental role of functional Cfl1 for the normal appearance of B cells and mast cells in mice.  The leukocyte-specific actin-bundling protein LPL is involved in several processes important for immunity, such as T cell motility and activation. LPL phosphorylation at serine-5 (S5) can increase its actin-binding and -bundling activity. In order to clarify the impact of LPL-S5 phosphorylation for B cells and mast cells, knock-in mouse lines expressing a non-phosphorylatable LPL form instead of the wildtype protein in B cells or mast cells were characterized in this thesis. In the mutant protein S5 was exchanged by non-phosphorylatable alanine (LPL-S5A). LPL-S5A expression in CTMCs led to a diminished peritoneal mast cell population. However, these mice showed a normal reaction in the in vivo model for systemic anaphylaxis. Mice expressing LPL-S5A B cell-specifically possessed a decreased splenic B cell number. The number of follicular B cells was moderately diminished while marginal zone B cells were nearly absent. In vitro experiments revealed an important role of LPL phosphorylation for chemokine-mediated migration of splenic B cells. The generated mouse lines allow to investigate whether LPL phosphorylation could be a leukocyte-specific target for immune modulation.
date: 2025
type: Dissertation
type: info:eu-repo/semantics/doctoralThesis
type: NonPeerReviewed
format: application/pdf
identifier: https://archiv.ub.uni-heidelberg.de/volltextserver/35509/1/Dissertation_JohannaKramer_PDF-A.pdf
identifier: DOI:10.11588/heidok.00035509
identifier: urn:nbn:de:bsz:16-heidok-355097
identifier:   Kramer, Johanna  (2025) The role of the actin-remodeling proteins L-plastin and cofilin-1 in mast cells and B cells.  [Dissertation]     
relation: https://archiv.ub.uni-heidelberg.de/volltextserver/35509/
rights: info:eu-repo/semantics/openAccess
rights: http://archiv.ub.uni-heidelberg.de/volltextserver/help/license_urhg.html
language: eng