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Asymmetrical B cell division: origin and functional significance

Final Report Summary - ASYMMETRY IN B CELLS (Asymmetrical B cell division: origin and functional significance.)

After antigen encounter, the immune system initiates a complex response during which antibodies and memory cells are generated. B lymphocytes play a key function in this process. They become fully activated after recognising the antigen through the B cell receptor (BCR). Once the antigen is recognised, it is internalised and processed, and presented back on the surface of the B cell.
The internalised antigen is polarised towards a specific location in the cell architecture (the microtubule organising centre), and, interestingly, it is kept there over time, resulting into an asymmetrical distribution between daughter cells once the cell enters into mitosis. The differing amount of antigen inherited by daughter cells seems to bias them towards playing different roles in the immune system.
The overall aim of this proposal was to understand how antigen polarity is established and maintained, giving rise to asymmetrical B cell division, as well as exploring the functional meaning of this asymmetry. More specifically, the project objectives were:
• How is antigen polarisation established and maintained following BCR-mediated internalisation?
• What is the function of polarity establishment in B cells?
• How does the asymmetric segregation of antigen influence the outcome of B cell differentiation in vivo?
• Are there other factors asymmetrically segregated in B cells?

During the course of this project we have developed state of the art techniques (confocal microscopy, flow cytometry and Image Stream) to quantify antigen polarity in B cells. This has allowed us to pinpoint microtubules and Protein kinase C (PKC) beta as key elements in the establishment and maintenance of polarity in B cells. Also, we have shown that such a polarity is essential to mount a productive immune response, being key for antigen presentation to cognate T cells and the initiation of the germinal centre reaction. Furthermore, we have seen that PKC beta has an intrinsic function in controlling the appearance of antibody producing cells (plasma cells), independently of antigen polarity.

The results from this project will not only contribute to the general knowledge of immunological responses, but will also explain more precisely how an important molecule such as PKC beta plays its role in B cells; controlling the emergence of the various B cell populations that are originated after B cell activation. Also, when considering that PKC beta is implicated in several types of cancer (such as chronic lymphocytic leukaemia, chronic myeloid leukaemia, acute myeloid leukaemia, etc.) the outcome of this project has a potential impact on the fight against cancer.