B cell activation triggered by the formation of the small receptor cluster: a computational study

• Published in: PLoS computational biology 2011-10, Vol.7 (10), p.e1002197-e1002197
• Main Authors: Hat, Beata, Kazmierczak, Bogdan, Lipniacki, Tomasz
• Format: Article
• Language: English
• Subjects: B cells; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; Biology; Cell Membrane - immunology; Cell Membrane - metabolism; Computational Biology; Cytoplasm; Grants; Humans; Immune response; Immunological Synapses - metabolism; Immunology; Lymphocyte Activation; Mathematics; Models, Immunological; Phosphorylation; Physiological aspects; Propagation; Protein kinases; Proteins; Receptor Aggregation - immunology; Receptors, Antigen, B-Cell - chemistry; Receptors, Antigen, B-Cell - metabolism; src-Family Kinases - metabolism
• ISSN: 1553-7358; 1553-734X; 1553-7358
• DOI: 10.1371/journal.pcbi.1002197

We proposed a spatially extended model of early events of B cell receptors (BCR) activation, which is based on mutual kinase-receptor interactions that are characteristic for the immune receptors and the Src family kinases. These interactions lead to the positive feedback which, together with two nonlinearities resulting from the double phosphorylation of receptors and Michaelis-Menten dephosphorylation kinetics, are responsible for the system bistability. We demonstrated that B cell can be activated by a formation of a tiny cluster of receptors or displacement of the nucleus. The receptors and Src kinases are activated, first locally, in the locus of the receptor cluster or the region where the cytoplasm is the thinnest. Then the traveling wave of activation propagates until activity spreads over the whole cell membrane. In the models in which we assume that the kinases are free to diffuse in the cytoplasm, we found that the fraction of aggregated receptors, capable to initiate B cell activation decreases with the decreasing thickness of cytoplasm and decreasing kinase diffusion. When kinases are restricted to the cell membrane - which is the case for most of the Src family kinases - even a cluster consisting of a tiny fraction of total receptors becomes activatory. Interestingly, the system remains insensitive to the modest changes of total receptor level. The model provides a plausible mechanism of B cells activation due to the formation of small receptors clusters collocalized by binding of polyvalent antigens or arising during the immune synapse formation.