Abstract
The activation and differentiation of T-cells are mainly directly by their co-regulatory receptors. T lymphocyte-associated protein-4 (CTLA-4) and programed cell death-1 (PD-1) are two of the most important co-regulatory receptors. Binding of PD-1 and CTLA-4 with their corresponding ligands programed cell death-ligand 1 (PD-L1) and B7 on the antigen presenting cells (APC) activates two central co-inhibitory signaling pathways to suppress T cell functions. Interestingly, recent experiments have identified a new cis-interaction between PD-L1 and B7, suggesting that a crosstalk exists between two co-inhibitory receptors and the two pairs of ligand-receptor complexes can undergo dynamic oligomerization. Inspired by these experimental evidences, we developed a coarse-grained model to characterize the assembling of an immune complex consisting of CLTA-4, B7, PD-L1 and PD-1. These four proteins and their interactions form a small network motif. The temporal dynamics and spatial pattern formation of this network was simulated by a diffusion-reaction algorithm. Our simulation method incorporates the membrane confinement of cell surface proteins and geometric arrangement of different binding interfaces between these proteins. A wide range of binding constants was tested for the interactions involved in the network. Interestingly, we show that the CTLA-4/B7 ligand-receptor complexes can first form linear oligomers, while these oligomers further align together into two-dimensional clusters. Similar phenomenon has also been observed in other systems of cell surface proteins. Our test results further indicate that both co-inhibitory signaling pathways activated by B7 and PD-L1 can be down-regulated by the new cis-interaction between these two ligands, consistent with previous experimental evidences. Finally, the simulations also suggest that the dynamic and the spatial properties of the immune complex assembly are highly determined by the energetics of molecular interactions in the network. Our study, therefore, brings new insights to the co-regulatory mechanisms of T cell activation.
Highlights
The activation of T cells is induced after the engagement of T cell receptors (TCR) with major histocompatibility complexes (MHC) presented on the surfaces of antigen presenting cells (APC) [1]
As we introduced in the Model and Methods, cytotoxic T lymphocyte-associated protein-4 (CTLA-4) receptors preexist as symmetric homodimers
200 CTLA-4 receptor dimers were randomly placed on the surface of T cell, while another 200 B7 were distributed on the opposite side of APC surface
Summary
The activation of a T cell can be regulated by the receptors on its surface, such as CTLA-4 and PD-1. Recent experiments discovered that the ligands of these two receptors, B7 and PD-L1, can interact with each other on the same surface of antigen presenting cells. Ligand and receptors randomly diffuse within this interface area. They further involve in different types of interactions, with each other from the same side or the opposite side of cell surface. Using this method, we found ligands and receptors can form complexes, and aggregate into large-scale clusters. This study, offers new insights to our understanding of signal regulation in T cells
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