Einfluss von CD152-Signalen auf das Migrationsverhalten von TH1-Lymphozyten

Autor :Karin Knieke
Herkunft :OvGU Magdeburg, Fakultät für Naturwissenschaften
Datum :02.02.2011
Dokumente :
Dataobject from HALCoRe_document_00010385
Typ :Dissertation
Format :Text
Kurzfassung :Postitioning of antigen-primed T cells in secundary lymphoid tissues and at sites of antigenic challenge is a mandatory requirement for functional adaptive immune responses. Localisation of cells is induced by chemokine-chemokinereceptor interactions. Here, the impact of the costimulatory molecule CD152 on the migratory capacity of inflammatory Th1 cells was analysed. Primary CD4+ T cells were differentiated into TH1 cells and migration was measured in vitro by chemotaxis assays in transwell systems. Genetic deficiency of CD152 (CD152-/-) reduced chemotaxis of TH1 cells towards the homeostatic chemokines CCL19 and CXCL12 and the pro-inflammatory chemokine CCL4. CD4+ TH1 cells showed the same results after polyclonally T cell receptor (TCR) stimulation as antigenspecific activation of TCR-transgenic CD152-/- CD4+ TH1 cells. Serological inactivation of CD152 by specific Fab-fragments confirmed increased migration of TH1 cells in the presence of CD152. Defined CD152-signals given by antibody-coupled microspheres and the reconstitution of CD152 in CD152-deficient cells by retroviral transduction of CD152-cDNA demonstrated, that CD152-signals can enhance chemokine-induced migration even in activated TH1 cells. Elevation of CD152-expression on CD4+ TH1 cells induced by strong TCR-activation through high levels of antigen or by antigenpresentation through dendritic cells correlated with augmented chemotactic response of TH1 cells. The study illustrated that the expression of chemokine receptors does not generally display the functional migration. CD152-signals induced the surface expression of CCR7 and CCR5 but not of CXCR4. Analysis of signaltransduction pathways of CCR5 in TH1 cells with or without CD152-signals revealed Gαi-protein dependent processes. CD152-engagement led to CCL4-induced inactivation of G-protein-coupled-kinase-2 and PI3’K-dependent Akt-activation. Adoptive transfers of radioactively labeled TH1-cells were used for in vivo studies of migration behaviour. Transferred TH1 cells supported the relevance of CD152-signals for the localisation of T cells, because increased levels of CD152-positive cells were found in lymph nodes and in inflamed tissue after induction of an infection in the delayed type hypersensitivity model (DTH). These data represent the plasticity of CD152-signals. CD152 does not only perform inhibitory responsibilities, moreover it directs T cells for proper localisation in draining lymphnodes and inflamed tissues. This novel function adds to the known importance of CD152-engagement in the control of peripheral immune responses. Therefore CD152 could be of therapeutic interest by regulating cellular compositions at sites of antigenic challenge.
Schlagwörter :CD152/CTLA-4, TH1-cells, chemokine receptor, migration
Rechte :Dieser Text ist urheberrechtlich geschützt
Größe :114 S.
Erstellt am :29.03.2011 - 08:23:44
Letzte Änderung :29.03.2011 - 08:24:16
MyCoRe ID :HALCoRe_document_00010385
Statische URL :http://edoc.bibliothek.uni-halle.de/servlets/DocumentServlet?id=10385