"Computational Modeling of Immunological Synapse Formation
and Affinity Discrimination in B Cells"
Post-Doctoral Researcher, Department of Biomedical Engineering, University of California, Davis
B cells, the cells responsible for antibody production, are activated by recognizing foreign antigen through the B cell antigen receptor (BCR) located on their surface. Advances in imaging and cell culture techniques have led to the discovery of complex new phenomena such as the immunological synapse and affinity discrimination. The immunological synapse is a concentric protein segregation structure that has been observed to form in the cell-cell contact region between B cells and antigen presenting cells (APCs) at the initial moment of contact. In B cells, the immunological synapse consists of a central cluster of BCR/Antigen complexes, surrounded by a ring of other receptor-ligand complexes such as co-receptor complexes and integrin-integrin complexes. Using an agent-based Monte Carlo procedure, we show that immunological synapse formation is crucially dependent on directed transport of BCR-antigen complexes towards the center of the B cell-APC contact zone, and to a lesser extent on receptor-ligand bond properties.
B cells are known to generate a signaling response that is proportional to the affinity with which the BCR binds antigen, a phenomenon known as “affinity discrimination”. B cell affinity discrimination is critical to the process of affinity maturation that results in the production of high affinity antibodies for immunological memory, and is thus important in applications such as vaccine design. Using a three-dimensional, agent-based stochastic simulation procedure of B cell receptor-ligand dynamics and intracellular signaling, we show that affinity discrimination can arise from the formation of BCR oligomers. It is known that BCRs form oligomers upon encountering antigen, and that the size and rate of formation of these oligomers increase with affinity. In our simulation, we have introduced a requirement that only BCR-antigen complexes that are part of an oligomer can engage cytoplasmic signaling molecules such as Src-family kinases. Our simulation shows that as affinity increases, BCR signaling activity increases in addition to the number of collected antigen. Our results are consistent with the existence of an experimentally-observed threshold affinity of activation at KA=105-106 M-1 (no signaling activity below this affinity value) and affinity discrimination ceiling of KA=1010 M-1 (no affinity discrimination above this affinity value). Further comparison with experiments shows that the time scale of dimer formation predicted by our model (less than 10 s) is well within the experimentally-observed time scale of BCR association with Src-family kinases (10-20 s).
Philippos Tsourkas obtained his Ph.D. in Mechanical Engineering from the University of California, Berkeley in December of 2004, with a concentration in genetic algorithms and bioheat transfer, under the supervision of Dr. Boris Rubinsky. Beginning in February of 2005, he worked as a post-doctoral scholar in the laboratory of Dr. Subhadip Raychaudhuri in the Department of Biomedical Engineering at the University of California, Davis, developing mathematical models for understanding important B cell functions such as immunological synapse formation and affinity discrimination. Starting August 2008, he fulfilled mandatory military service in Greece, resuming his research activities at UC Davis in March of 2009. Since March of 2012 he has been working as a researcher at the Curie Institute in Paris, France, in the laboratory of Dr. Vasili Soumelis, developing algorithms for data analysis of high-throughput DNA microarray experiments geared towards understanding how dendritic cells integrate multiple, and often conflicting, environmental stimuli. He is also working on mathematical modeling of the interaction between HIV, CD4+ T cells, and plasmacytoid dendritic cells.