A theoretical framework for quantitative analysis of the molecular basis of costimulation
Jansson A, Barnes E, Klenerman P, Harlén M, Sørensen P, Davis SJ, Nilsson P. (2005), J Immunol. 175, 1575-85
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 approximately 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.
Key figure: Complex formation in the free-diffusion model
A, Numbers of CD28 molecules bound to B7-1 or B7-2 at the synapse between a naive T cell and an iDC or a mDC. B, Numbers of CD28 and CTLA-4 molecules bound to B7-1 or B7-2 at the synapse between an activated T cell and a mDC. C, Total numbers of complexed CD28 and CTLA-4 molecules at the synapse between an activated T cell and a mDC. D, Numbers of bound CTLA-4 and B7-1 molecules forming multivalent arrays consisting of 1-6, 7-12, 13-18, and >18 bound CTLA-4 molecules. Simulations were run using the parameter values listed in Tables III-V.