A theoretical framework for quantitative analysis of the molecular basis of costimulation.
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.
Jansson
Andreas
A
Computational Biology, School of Life Sciences, University of Skövde, Skövde, Sweden.
Barnes
Eleanor
E
Klenerman
Paul
P
Harlén
Mikael
M
Sørensen
Poul
P
Davis
Simon J
SJ
Nilsson
Patric
P
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D015703:Antigens, CD / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism; D000943:Antigens, Differentiation / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism; D018122:B7-1 Antigen / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism; D051940:B7-2 Antigen; D001693:Biological Transport, Active / Q000276:immunology; D018106:CD28 Antigens / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism; D060908:CTLA-4 Antigen; D002450:Cell Communication / Q000276:immunology*; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D003198:Computer Simulation; D003713:Dendritic Cells / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism; D018448:Models, Immunological; D011485:Protein Binding / Q000276:immunology; D025941:Protein Interaction Mapping / Q000379:methods; D021381:Protein Transport / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000737:chemistry / Q000276:immunology / Q000378:metabolism
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; C497964:CD86 protein, human; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D008024:Ligands; D008562:Membrane Glycoproteins