- The Major Histocompatibility Complex class I (MHC-I) is a type I membrane protein expressed at the surface by virtually all cell types. MHC-I is loaded in the endoplasmic reticulum (ER) with peptides derived from cytosolic proteins and presents them on the plasma membrane to T-cells. This constitutes the primary mechanism by which most nucleated cells report on possible infection by pathogen or damaged tissue.Many studies have shown that the lateral mobility of membrane proteins, and particularly MHC-I, is hindered, creating a membrane with heterogeneous distribution of its components. Using Near-field Scanning Optical Microscopy (NSOM), we have shown that MHC-I is found in clusters, ∼300 - 700 nm in diameter, on the plasma membrane of cells. Since obstructed lateral diffusion alone cannot explain the maintenance of clusters at steady state, we proposed a model that accounts for plasma trafficking, to explain the persistence of the clusters.The model predicts dynamic clusters of MHC-I, created at an instant, by vesicle delivery, and decaying slowly by hindered diffusion over barriers.We proved the dynamic nature of MHC-I clusters, and characterized their life-time, using GFP-tagged molecules and Total Internal Reflection Fluorescence Microscopy (TIRFM). Furthermore, since potential barriers to lateral diffusion have been previously suggested as actin filaments, we have recently shown that the life-time of MHC-I clusters can be elongated by strengthening these barriers and shortened by weakening them. We have also characterized the rate of MHC-I trafficking to the plasma membrane, and have developed a simple way to reduce it; the effect is dispersion of the MHC-I clusters, as predicted by the model.In the next step we will question the effect of all the dynamic parameters on the recognition of the immune system.