Lipid rafts and T-lymphocyte function: implications for autoimmunity

Abstract

Experimental evidence indicates that the mammalian cell membrane is compartmentalized. A structural feature that supports membrane segmentation implicates assemblies of selected lipids broadly referred to as lipid rafts. In T-lymphocytes, lipid rafts are implicated in signalling from the T-cell antigen receptor (TCR) and in localization and function of proteins residing proximal to the receptor. This review summarizes the current literature that deals with lipid raft involvement in T-cell activation and places particular emphasis in recent studies investigating lipid rafts in autoimmunity. The potential of lipid rafts as targets for the development of a new class of immune-modulating compounds is discussed.

Fig. 1

A model that correlates changes in the plasma membrane with TCR stimulation. In non-stimulated T-cells, the TCR is in monomeric form and its interaction with lipid rafts is transitory and unable to initiate signalling. Upon antigenic challenge, the reorganization of actin cytoskeleton results in formation of TCR microclusters and reduces the mobility of lipid rafts thus creating an environment conducive to long-lasting interactions. Concomitantly, the activity of Lck in lipid rafts increases owing to the action of a pool of CD45 molecules that moves to close proximity. These changes favour phosphorylation of ITAMs and initiation of signalling.

Fig. 2

A schematic model for the regulation of Lck activity in T-cells. The activity of Lck in lipid rafts is low owing to the recruitment of Csk by PAG/Cbp, LIME and possibly an additional, as yet unknown, adaptor to these domains. Movement of Lck out of lipid rafts or transient association of lipid rafts with CD45 could result in Y-505 dephosphorylation and increase in Lck activity.

Fig. 3

Changes in the membrane of lupus T-cells may associate with their autoimmune phenotype. The higher cholesterol and GM1 content of lupus T-cell membrane may result in larger and/or less mobile lipid rafts. This in combination with the increased association of CD45 with lipid rafts, higher Lck activity, and changes in the actin cytoskeleton seen in these cells could reduce the threshold for activation.