Lipid Rafts & Co.: an integrated model of membrane organization in T cell activation.
ABSTRACT The model of membrane compartmentalization by self-organizing functional lipid microdomains, named lipid rafts, has been a fruitful concept resulting in great progress in understanding T cell signal transduction. However, due to recent results it has become clear that lipid rafts describe only one out of several membrane organizing principles crucial for T cell activation besides fences and pickets and protein-protein interactions that take part in the formation of the immunological synapse as a highly organized structure at the T cell contact site to the antigen-presenting cell. This review describes the concepts of lipid rafts and other membrane organizing principles to evolve a novel integrated model on the functional role of microdomains in immunological synapse formation and T cell activation. Further research has to elucidate the relative contribution and interrelation of different modes of membrane organization in productive T cell activation.
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ABSTRACT: Polyunsaturated fatty acids (PUFAs), notably of the n-3 series, have immunosuppressive effects which make these molecules candidates for treating inflammatory symptoms associated with cardiovascular disease, obesity, arthritis, and asthma. However, immunosuppression by PUFAs could increase susceptibility to bacterial and viral infection. A detailed molecular picture is required in order to understand the balance between the benefits and risks of utilizing PUFAs as adjuvant immunosuppressants. Here we review evidence that incorporation of PUFAs into membrane lipids of antigen presenting cells (APCs) downregulates APC function. We propose that PUFAs modulate antigen presentation by altering the organization of lipid and protein molecules of the plasma membrane and endomembranes; this alters recognition and responses by T cells. The foundation of our hypothesis is built on data from artificial bilayer experiments which provide the physical principles by which PUFA acyl chains affect membrane architecture. This review also reconciles conflicting results in the literature by discussing the advantages and disadvantages of differing methods of PUFA treatment of cells. We suggest that membrane modulation of immune cells may be an important and overlooked mechanism of immunomodulation. In addition, we propose that mechanistic studies with defined experimental protocols will speed the translation of laboratory studies on PUFAs to the clinic.Chemistry and Physics of Lipids 06/2008; 153(1):24-33. DOI:10.1016/j.chemphyslip.2008.02.008 · 2.59 Impact Factor
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ABSTRACT: The interaction between transmembrane proteins, lipids, and cytoskeletal components provides a framework for the compartmentalization of the cell surface. Intense research has focused on lipid rafts, the cholesterol-enriched membrane microdomains containing many signalling molecules. However, recent advances in cellular and molecular imaging have challenged prevailing models on the role of these membrane microdomains in signal transduction and their biological significance in cell physiology. Using the T lymphocyte as an example, we review here some of the current developments in our understanding of compartmentalization of signalling. T cells are useful to study this issue given the confluence of knowledge about the morphology associated with early signalling, about the kinetics of antigen receptor engagement, and about the resulting events leading to activation of these cells. Specifically, activation of the T cell upon T cell receptor (TCR) engagement with specific peptide: major histocompatibility complex (MHC) molecule complexes on the surface of antigen-presenting cells (APC) results in a coordinated redistribution of some cell surface proteins into a morphological structure known as the immunological synapse (IS) within a timeline encompassing antigen receptor signalling. In the context of these events, we examine the potential interactions between cell surface receptors, protein-protein microclusters, and cytoskeletal networks that support the formation of TCR-dependent signalling units or signalosomes in signalling permissive environments.
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ABSTRACT: Long chain polyunsaturated fatty acids (PUFAs) are well-known for their beneficial immunomodulatory effects in a variety of autoimmune and inflammatory disorders. The underlying molecular mechanisms are manifold, but are still elusive to a large extent. Several cell types are target of PUFA action. In this chapter, the effects of PUFAs on T-cell activation and function are discussed. PUFAs directly affect T-cell signaling and thus activation as well as T-cell interactions with antigenpresenting cells (APCs). The mainstream of publications in the field describes alterations of the lateral membrane organization as crucial for PUFA action on T-cells. Therefore, this chapter includes a brief overview over the current understanding of membrane microdomains, so-called “lipid rafts,” and their role in T-cell signal transduction.