Protein Clusters on the T Cell Surface May Suppress Spurious Early Signaling Events

Abstract

T cells play an important role in the adaptive immune system, quickly activating effector functions in response to small numbers of antigenic peptides but rarely activating in response to constant interaction with most endogenous peptides. Emerging experimental evidence suggests that key membrane-bound signaling proteins such as the T cell receptor and the adaptor protein Lat are spatially organized into small clusters on the T cell membrane. We use spatially resolved, stochastic computer simulations to study how the inhomogeneous distribution of molecules affects the portion of the T cell signaling network in which the kinase ZAP-70, originating in T cell receptor clusters, phosphorylates Lat. To gain insight into the effects of protein clustering, we compare the signaling response from membranes with clustered proteins to the signaling response from membranes with homogeneously distributed proteins. Given a fixed amount of ZAP-70 (a proxy for degree of TCR stimulation) that must diffuse into contact with Lat molecules, the spatially homogeneous system responds faster and results in higher levels of phosphorylated Lat. Analysis of the spatial distribution of proteins demonstrates that, in the homogeneous system, nearest ZAP-70 and Lat proteins are closer on average and fewer Lat molecules share the same closest ZAP-70 molecule, leading to the faster response time. The results presented here suggest that spatial clustering of proteins on the T cell membrane may suppress the propagation of signal from ZAP-70 to Lat, thus providing a regulatory mechanism by which T cells suppress transient, spurious signals induced by stimulation of T cell receptors by endogenous peptides. Because this suppression of spurious signals may occur at a cost to sensitivity, we discuss recent experimental results suggesting other potential mechanisms by which ZAP-70 and Lat may interact to initiate T cell activation.