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.
Highlights
In order for the immune system to effectively neutralize pathogens, cells must take part in complex cell-cell communication interactions, such as those occurring between T or B cells and antigen presenting cells (APCs), such as dendritic cells
It has become widely accepted that actively signaling T cell receptor (TCR) molecules are more likely to be found in the distal regions of the synapse and subsequently migrate into the central SMAC (cSMAC) [2,3,4]
Whilst macroscale organization is observed in B and NK cells, they form their own uniquely structured immunological synapse (IS) for their specific functions
Summary
In order for the immune system to effectively neutralize pathogens, cells must take part in complex cell-cell communication interactions, such as those occurring between T or B cells and antigen presenting cells (APCs), such as dendritic cells. It was recently found that following cell treatment with the naturally occurring analog cholesterol sulfate, TCR nanoclusters were disrupted, leading to reduced avidity for peptide-MHC and reduced CD3 ITAM phosphorylation [38] This points the way toward potential manipulation of membrane lipids in order to control molecular distributions (clustering) and function and, lymphocyte signaling. In addition to regulating protein distributions and function, high lipid tail order has been proposed to play a protective role for cytotoxic CD8+ T cells, protecting against accidental death by repelling perforin [41] In these cells, phosphatidylserine is enriched at the immunological synapse following antigen recognition [42]. Many of these are involved in regulating membrane order and, might be relevant to human health and disease [57] including cancer and autoimmune disease
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