Links between activation and cytoskeletal regulation of B lymphocytes

• Interplay between adhesion molecules and the cytoskeleton is involved in many aspects of B lymphocyte behaviour during an immune response. Events such as cell polarisation and locomotion, collaboration with T lymphocytes and segregation in secondary lymphoid tissues all include mechanisms that recognise microenvironment and accordingly adjust morphological features of the cell. Their role in the functions of the immune system is strengthened by devastating effects observed in the absence of adhesion molecules involved in lymphocyte extravasation or in a disease known as Wiskott-Aldrich syndrome. The latter deficiency is associated with mutations in Wiskott-Aldrich syndrome protein (WASP) that among other features manifest in a decreased villosity of leukocyte membranes, presumably due to abnormal actin polymerisation.The adhesive capacity of B cells is regulated by a variety of soluble and immobilised factors. In this thesis we concentrated our attention on the role of IL-4 and cross-linking of CD40. These stimuli partially mimic signals received during B and T lymphocyte collaboration and are critical for B cell differentiation. We found that both these stimuli increased LFA-1 dependent adhesion of B lymphocytes. Additionally, the extent of cell aggregation was correlated with an increased cell locomotion, spreading and induction of microvilli-like extensions of the plasma membrane. This indicates that IL-4 or cross-linking of CD40 induced global changes in plasticity of cortical cytoskeleton. The molecular mechanisms behind these changes are not clear in detail. However, we demonstrate that the transcription factor STAT6 is needed for IL-4 induced changes in morphology of B cells. Also, changes in cortical cytoskeleton induced by CD40 and IL-4 are partially dependent on intact Cdc42/WASP system. Our findings suggest that IL-4 or CD40 signaling operate different molecular machinery in regulation of cell surface architecture and also indicate that B cells possess WASP-independent ways to regulate cortical cytoskeleton.Homotypic adhesion of activated B lymphocytes can involve adhesion systems other than the LFA-1. Carcinoembryonic antigen related cell-cell adhesion molecule-1 (CEACAM1, CD66a) belongs to the Ig superfamily and mediates homotypic cell-cell interactions. Hypothetically, aggregation of B lymphocytes would favour homophilic adhesion systems. Surprisingly, antibodies to CEACAM1 upregulated LFA-1 mediated binding. Also, cross-linking of CEACAM1 on the surface of B lymphocytes co-stimulates B cell receptor (BCR) induced proliferation and supports the initial steps of B cell differentiation.Overall, our results indicate that B lymphocytes possess several mechanisms that control cortical cytoskeleton and the architecture of the cell surface, modulating adhesive interactions with surrounding cells. These adhesive interactions may influence signaling via BCR and the initial steps of B cell differentiation and survival.

Ämnesord

NATURVETENSKAP  -- Biologi (hsv//swe)

NATURAL SCIENCES  -- Biological Sciences (hsv//eng)

Nyckelord

Zoological Developmental Biology

zoologisk utvecklingsbiologi

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