Las Balsas De Lípidos En La Activación De Linfocitos

Microbes and Infection 6 (2004) 686–692 www.elsevier.com/locate/micinf

Review

Lipid rafts in lymphocyte activation
Paola Pizzo a,*, Antonella Viola a,b
a

Department of Biomedical Sciences, University of Padova, Viale Giuseppe Colombo 3, I-35121 Padova, Italy b Venetian Institute of Molecular Medicine, via Orus 2, 35129 Padova, Italy Available online 15 April 2004

Abstract Theexistence of sphingolipid- and cholesterol-rich membrane microdomains called “lipid rafts”, as well as their role in lymphocyte biology, has been widely debated during the last few years. Plasma membrane microdomains seem to be primarily involved in initiation and propagation of the signal transduction cascade associated with lymphocyte activation. In this review, we discuss the recent literaturesuggesting that, during lymphocyte activation and chemotaxis, lipid rafts act as platforms to compartmentalise signalling and facilitate specific protein–protein interactions. © 2004 Elsevier SAS. All rights reserved.
Keywords: Rafts; Immunoreceptor triggering; Membrane domains; Lymphocyte signalling

1. The lipid raft model Biological membranes are composed of lipids and proteins associated bynon-covalent interactions. Lipid molecules are organised in a fluid bilayer due to hydrophobic forces, to minimise their contact with water. This principle also applies to the insertion of transmembrane proteins into the bilayer: that is, proteins are arranged so that their hydrophobic surfaces are hidden among lipids. In biological membranes, the two leaflets of the bilayer present different lipidcomposition, with the outer leaflet containing sphingolipids, glycosphingolipids and phospholipids, such as phosphatidylcholine, while the inner leaflet is mainly constituted of phospholipids, such as phosphatidylserine and phosphatidyletanolamine. The fluid mosaic model has recently been revisited and researchers have proposed that lipids are not randomly distributed in the bilayer, but patched to formdomains, named “rafts”, whose composition and physical state differ from the average for the bilayer (Fig. 1).

Abbreviations: APC, antigen-presenting cells; BCR, B cell antigen receptor; DRM, detergent-resistant membrane; FRET, fluorescence resonance energy transfer; GPI, glycosylphosphatidylinositol; ITAMs, immunoreceptor tyrosine-based activation motifs; LAT, linker for activation of T cells;MbCD, methyl-b-cyclodextrin; MHC, major histocompatibility complex; TCR, T cell receptor; ZAP-70, zeta-associated protein 70. * Corresponding author. Tel.: +39-049-827-6067; fax: +39-049-827-6049. E-mail address: paola.pizzo@unipd.it (P. Pizzo). © 2004 Elsevier SAS. All rights reserved. doi:10.1016/j.micinf.2004.02.017

The “lipid raft” model suggests that attractive forces between sphingolipidsand cholesterol mediate the formation of lateral lipid clusters in an unsaturated glycerolphospholipid environment [1,2]. Phospholipids and sphingolipids have distinct biophysical properties: (i) sphingolipids have longer and more-saturated fatty acid chains and exhibit stronger lateral cohesion than glycerolphospholipids; and (ii) sphingolipid alkyl chains preferentially interact with cholesterolwith respect to the unsaturated chains typical of phospholipids. Thus, these lipids behave in a different way when forming a monolayer, with sphingolipids showing a tendency to form distinct “liquid-ordered” phases dispersed in the “liquid-disordered” matrix formed by phospholipids [3]. Operationally, rafts have been defined as “detergentresistant membrane domains” (DRM), since they are insolublein cold detergent extraction and float to the top of a density gradient as a separable membrane fraction [4]. DRM do not represent lipid rafts in living cells, but may reflect aggregation of small/transient “in vivo” rafts, although the use of non-standardised extraction protocols generates major concerns about the method (see Table 1). Nevertheless, the fact that certain proteins are detergent...