Die Rolle der Bruton-Tyrosinkinase in murinen myeloiden dendritischen Zellen
Siebert, Lena Maria
Bruton´s tyrosine kinase (Btk) is mainly involved in B cell-receptor signaling and therefore plays a critical role for B cell development and function. Without Btk, B cells arrest in an early pre-B cell state. Mutations in the Btk gene cause XLA (X linked Agammaglobulinemia) in humans and Xid (X linked immunodeficiency) in mice, both mainly characterized by the loss of mature B cells, which leads to a severe immunodeficiency. It became evident that Btk-deficiency also affects the myeloid cell compartment. Especially, antigen presenting dendritic cells (DC) play a critical role for the function of immunity as they initiate appropriate immune responses to pathogens and link innate and adaptive immunity. Therefore, we evaluated the effect of Btk on myeloid DC with emphasis to their development, expression of surface-marker and ability to chemotaxis and T cell stimulation. Bone marrow-derived myeloid DC were generated in the presence of GM-CSF (granulocyte macrophage colony-stimulating factor) and stimulated by the ligands of Toll-like receptor (TLR) TLR3 (Poly I:C),TLR 4 (LPS), TLR7/8 (Imiquimod) and TLR9 (ODN). Our data indicate, that generation-efficiency of bone marrow-derived myeloid DC is impaired without Btk function. Furthermore, Btk-Knockout DC showed potentially reduced expression-levels of MHC-II, CD54 (ICAM 1) and CD184 (CXCR4), but potentially increased expression-levels of CD11a, CD18, CD43, CD44 and CD197 (CCR7). Also chemotactic migration stimulated by the signals of MIP-3 beta und SDF 1 alpha was impaired in Btk-Knockout DC. We further demonstrated that DC might show enhanced stimulation of T cells without Btk-function. Analysis of different TLR-stimulations revealed a role for Btk in MyD88-dependent as well as in MyD88-independent TLR-signaling pathways.
Subject HeadingsAntikörpermangelsyndrom [GND]
Dendritische Zelle [GND]
Ammaglobulinaemia tyrosine kinase [MeSH]
Dendritic cells [MeSH]