The Role of Protein and Lipid Clustering in Lymphocyte Activation

Abstract

Lymphocytes must strike a delicate balance between activating in response to signals from potentially pathogenic organisms and avoiding activation from stimuli emanating from the body's own cells. For cells, such as T or B cells, maximizing the efficiency and fidelity, whilst minimizing the crosstalk, of complex signaling pathways is crucial. One way of achieving this control is by carefully orchestrating the spatiotemporal organization of signaling molecules, thereby regulating the rates of protein-protein interactions. This is particularly true at the plasma membrane where proximal signaling events take place and the phenomenon of protein microclustering has been extensively observed and characterized. This review will focus on what is known about the heterogeneous distribution of proteins and lipids at the cell surface, illustrating how such distributions can influence signaling in health and disease. We particularly focus on nanoscale molecular organization, which has recently become accessible for study through advances in microscope technology and analysis methodology.

Keywords: B cell synapse; T cell synapse; lipid rafts; lymphocytes; nano-clustering.

Figure 1

Illustration of different molecule (protein or lipid) distributions on the cell surface. For dispersed distributions, the average distance between molecules is larger than would be expected for randomly distributed molecules. In both the clustered examples shown here, the average nearest neighbor distance is smaller than expected for randomly arranged molecules.

Figure 2

Hypothesized effect of molecular nanoclustering on input-output relationship of a generalized signaling pathway for two proteins. A hypothetical kinase for example (red) can diffuse in the membrane and phosphorylate a substrate with different clustering properties (blue, green, yellow). The input can be conceptualized simply—as the amount of active kinase or more generally—say as the strength of antigen binding by a receptor. The output might be proximal downstream phosphorylation levels more distal, such as gene expression—analogous to the rate of production of product in a chemical reaction. The shape of the curve relating these two depends on the stoichiometry, oligermerisation and cooperativity of the molecules involved, just like a classical chemical reaction. In a cell signaling pathway however the situation will be complex, with many interacting partners, feedback and so on. The exact shapes of such hypothetical curves therefore remain an area for future study.