Regulation of cell morphology and adhesion in B lymphocytes by interleukin-4
Author: Davey, Edward
Date: 2000-11-02
Location: Föreläsningssalen D224, CMB, von Eulers väg 3
Time: 10.00
Department: Institutionen för cell- och molekylärbiologi (CMB) / Department of Cell and Molecular Biology
Abstract
The different stages in lymphocyte differentiation and activation are associated with profound changes in cell morphology. Under normal development, lymphocytes are at different times in direct contact with stromal cells and extracellular matrix, they transverse endothelium, are transported via blood and lymphatic vessels, home to specific lymphoid organs and may undergo antigen-driven activation events. All of such events are associated with characteristic changes in cell morphology reflecting the importance of appropriate regulation of cytoskeleton for such processes.
The regulation of activation in B lymphocytes is influenced by a variety of soluble and membrane bound factors. IL-4 is a cytokine that profoundly influences the outcome of an immune response. It is capable of exerting many powerful effects on B lymphocytes. The best described activity of IL-4 on B cells is perhaps in inducing immunoglobulin class switching. It is also capable of up-regulating the expression of cell surface molecules such as CD23 and MHC class II as well as acting synergistically in inducing cell proliferation. Lymphocyte activation is often accompanied by an increased capacity for cell adhesion and cell locomotion during which cells undergo profound changes in cell morphology. IL-4 has been found to modulate these activities.
This thesis addresses the question of how IL-4 regulates B cell adhesion and focuses closely on induced changes in cell morphology and how these may influence cell adhesion. B cells stimulated with LPS and IL-4 display increased levels of cell aggregation as compared to cells stimulated with LPS alone. The mechanism by which IL-4 modulates B-cell adhesion is not fully understood. Many B cell mitogens have been reported to induce adhesion that is mediated largely through the interaction of LFA-1 and ICAM-1. However, IL-4 does not appear to significantly alter the expression levels of either LFAI or ICAM- 1, neither does it alter the affinity of LFA-1. We initially examined the role CD23 in B cell adhesion. CD23 has been described as an adhesion molecule, the expression of which is significantly increased by IL-4. We found however, no evidence for CD23 influencing IL-4 induced B cell adhesion.
LPS plus IL-4 stimulated B cells aggregate in tight cell clusters that are morphology distinct from cell aggregates induced by LPS alone. Spread cells are also seen preferentially in LPS plus IL-4 stimulated cultures. Using an assay to assess cell spreading, where the tissue culture wells were coated with antibodies, the majority of B cells were found to spread, forming long dendrites when treated with LPS plus IL-4. Examination at an ultrastructural level using electron microscopy revealed induction of ribosome-containing dendrites and rnicrovilli-like structures in both spread and aggregated cells, stimulated with LPS and IL-4. Cell-cell contacts were frequently made by microvilli in aggregated cells. A similar phenomenon was observed in cells stimulated with anti-CD40. Thus, such morphology changes correlate closely to cell adhesion. Furthermore, immuno-electron microscopy revealed that ICAM- I was expressed on the induced microvilli-like structures. Heterotypic adhesion assays show that the action of IL-4 or anti-CD40 on B cells results in cell adhesion being more LFA-1 dependent and suggests a mechanism involving altered ICAM-1 presentation on B cells. STAT6 deficient mice were used to address the question of the role of STAT6 in this process. Mild to severe impairment was observed in different assays measuring changes in cell morphology, in the absence of STAT6. Cell adhesion was likewise mildly impaired. In conclusion, this study shows that IL-4 has profound effects on the morphology of B lymphocytes. A novel mechanism is proposed by which IL-4 may regulate the adhesive capacity of B cells via the induction of ICAM-1 bearing microvilli. Furthermore, the possibility that IL-4 could influence how B cells communicate with other cells in close contact by presenting cell surface molecules on induced membrane extensions, is an interesting notion that is still largely unexplored.
The regulation of activation in B lymphocytes is influenced by a variety of soluble and membrane bound factors. IL-4 is a cytokine that profoundly influences the outcome of an immune response. It is capable of exerting many powerful effects on B lymphocytes. The best described activity of IL-4 on B cells is perhaps in inducing immunoglobulin class switching. It is also capable of up-regulating the expression of cell surface molecules such as CD23 and MHC class II as well as acting synergistically in inducing cell proliferation. Lymphocyte activation is often accompanied by an increased capacity for cell adhesion and cell locomotion during which cells undergo profound changes in cell morphology. IL-4 has been found to modulate these activities.
This thesis addresses the question of how IL-4 regulates B cell adhesion and focuses closely on induced changes in cell morphology and how these may influence cell adhesion. B cells stimulated with LPS and IL-4 display increased levels of cell aggregation as compared to cells stimulated with LPS alone. The mechanism by which IL-4 modulates B-cell adhesion is not fully understood. Many B cell mitogens have been reported to induce adhesion that is mediated largely through the interaction of LFA-1 and ICAM-1. However, IL-4 does not appear to significantly alter the expression levels of either LFAI or ICAM- 1, neither does it alter the affinity of LFA-1. We initially examined the role CD23 in B cell adhesion. CD23 has been described as an adhesion molecule, the expression of which is significantly increased by IL-4. We found however, no evidence for CD23 influencing IL-4 induced B cell adhesion.
LPS plus IL-4 stimulated B cells aggregate in tight cell clusters that are morphology distinct from cell aggregates induced by LPS alone. Spread cells are also seen preferentially in LPS plus IL-4 stimulated cultures. Using an assay to assess cell spreading, where the tissue culture wells were coated with antibodies, the majority of B cells were found to spread, forming long dendrites when treated with LPS plus IL-4. Examination at an ultrastructural level using electron microscopy revealed induction of ribosome-containing dendrites and rnicrovilli-like structures in both spread and aggregated cells, stimulated with LPS and IL-4. Cell-cell contacts were frequently made by microvilli in aggregated cells. A similar phenomenon was observed in cells stimulated with anti-CD40. Thus, such morphology changes correlate closely to cell adhesion. Furthermore, immuno-electron microscopy revealed that ICAM- I was expressed on the induced microvilli-like structures. Heterotypic adhesion assays show that the action of IL-4 or anti-CD40 on B cells results in cell adhesion being more LFA-1 dependent and suggests a mechanism involving altered ICAM-1 presentation on B cells. STAT6 deficient mice were used to address the question of the role of STAT6 in this process. Mild to severe impairment was observed in different assays measuring changes in cell morphology, in the absence of STAT6. Cell adhesion was likewise mildly impaired. In conclusion, this study shows that IL-4 has profound effects on the morphology of B lymphocytes. A novel mechanism is proposed by which IL-4 may regulate the adhesive capacity of B cells via the induction of ICAM-1 bearing microvilli. Furthermore, the possibility that IL-4 could influence how B cells communicate with other cells in close contact by presenting cell surface molecules on induced membrane extensions, is an interesting notion that is still largely unexplored.
List of papers:
I. Davey EJ, Bartlett WC, Kikutani H, Fujiwara H, Kishimoto T, Conrad DH, Severinson E (1995). "Homotypic aggregation of murine B lymphocytes is independent of CD23" Eur J Immunol 25(5): 1224-9
Pubmed
II. Davey EJ, Thyberg J, Conrad DH, Severinson E (1998). "Regulation of cell morphology in B lymphocytes by IL-4: evidence for induced cytoskeletal changes" J Immunol 160(11): 5366-73
Pubmed
III. Greicius G, Davey EJ, Thyberg J, Severinson E (2000). "T cell dependent induction of microvilli on B cells correlates with increased adhesive capacity." (Submitted)
IV. Davey EJ, Greicius G, Thyberg J, Severinson E (2000). "STAT6 is required for the regulation of IL-4-induced cytoskeletal events in B cells. " Int Immunol 12(7): 995-1003
Pubmed
I. Davey EJ, Bartlett WC, Kikutani H, Fujiwara H, Kishimoto T, Conrad DH, Severinson E (1995). "Homotypic aggregation of murine B lymphocytes is independent of CD23" Eur J Immunol 25(5): 1224-9
Pubmed
II. Davey EJ, Thyberg J, Conrad DH, Severinson E (1998). "Regulation of cell morphology in B lymphocytes by IL-4: evidence for induced cytoskeletal changes" J Immunol 160(11): 5366-73
Pubmed
III. Greicius G, Davey EJ, Thyberg J, Severinson E (2000). "T cell dependent induction of microvilli on B cells correlates with increased adhesive capacity." (Submitted)
IV. Davey EJ, Greicius G, Thyberg J, Severinson E (2000). "STAT6 is required for the regulation of IL-4-induced cytoskeletal events in B cells. " Int Immunol 12(7): 995-1003
Pubmed
Issue date: 2000-10-12
Publication year: 2000
ISBN: 91-628-4429-6
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