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A Theoretical Framework for Quantitative Analysis of the Molecular Basis of Costimulation

Andreas Jansson^*,, Eleanor Barnes, Paul Klenerman, Mikael Harlén^*, Poul Sørensen^¶, Simon J. Davis^1, and Patric Nilsson^*

^* Computational Biology, School of Life Sciences, University of Skövde, Skövde, Sweden; School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, Australia; Nuffield Department of Clinical Medicine, Peter Medawar Building for Pathogen Research, University of Oxford, and Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom; and ^¶ LEO Pharma, Ballerup, Denmark

We present a theoretical framework for simulating the synaptic accumulation of the costimulatory molecules CD28, CTLA-4, B7-1, and B7-2, based on a system of mean-field, ordinary differential equations, and rigorous biophysical and expression data. The simulations show that binding affinity, stoichiometric properties, expression levels, and, in particular, competition effects all profoundly influence complex formation at cellular interfaces. B7-2 engages 33-fold more CD28 than CTLA-4 at the synapse in contrast to B7-1, which ligates 7-fold more CTLA-4 than CD28. Although B7-1 completely dominates interactions with CTLA-4, forming linear arrays of 7-18 receptor-ligand pairs, CTLA-4 is fully engaged by B7-2 when B7-1 is absent. Additional simulations reveal the sensitivity of CD28 interactions to modeled transport processes. The results support the concept that B7-2 and B7-1 are the dominant ligands of CD28 and CTLA-4, respectively, and indicate that the inability of B7-2 to recruit CTLA-4 to the synapse cannot be due to the differential binding properties of B7-1 and B7-2 only. We discuss the apparent redundancy of B7-1 in the context of a potentially dynamic synaptic microenvironment, and in light of functions other than the direct enhancement of T cell inhibition by CTLA-4.

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