Signalisation et transport intracellulaire des immunorécepteurs.

Abstract

Des recepteurs specifiques exprimes par les cellules immunocompetentes reconnaissent les antigenes : l' immunoglobuline membranaire exprimee par les lymphocytes B (BcR) les reconnait sous forme soluble ; le recepteur de l' antigene des lymphocytes T (TcR) reconnait le complexe peptide antigenique-CMH exprime a la surface des cellules presentatrices. D' autres recepteurs exprimes a la surface des macrophages ou des cellules dendritiques reconnaissent la partie constante des anticorps complexes a un antigene (FcR). La liaison de ces recepteurs a leurs ligands induit une cascade d' evenements aboutissant a l' activation des cellules et a l' internalisation des complexes formes dans des vesicules, qui sont ensuite transportes dans des endosomes et des lysosomes. Dans les cas du BcR et du FcR, il existe ainsi un ciblage des antigenes dans des compartiments specialises ou ils sont appretes et associes a des molecules du CMH de classe II puis presentes a la surface des cellules. Un couplage des phenomenes de signalisation et d' internalisation vient d' etre demontre au sein d' une meme unite moleculaire et fonctionnelle.

Cells of the immune system express a wide variety of receptors, defined as immunoreceptors. These receptors are involved in antigen recognition, B and T lymphocytes express clonally distributed receptors which recognize soluble antigen for the B cell receptor (BcR) or peptide associated to major histocompatibility complex (MHC) molecules for the T cell receptor (TcR). Moreover, B lymphocytes macrophages and dendritic cells, express receptors for antigen antibody complexes, which recognize the Fc portion of immunoglobulins (FcR). All these immunoreceptors share stricking functional and structural similarities. BcRs, TcRs and most FcRs are multichain complexes composed of a ligand binding module which consists of one or two chains determining the antigen specificity, and of a transducing module which consists of two to six chains containing one or several conserved motifs in their intracytoplasmic domain. These motifs called ITAM for immunoreceptor tyrosine-based activation motif couplereceptors to intracellular effectors, such as tyrosine kinases, which induce a cascade of events leading to cell activation. In parallel, expression of these immunoreceptors is finely regulated. These receptors are continuously and constitutively being internalized and recycled back to the cell surface. Moreover, recognition of the antigen by these immunoreceptors leads to the downregulation of the triggered receptors which are all internalized and transported along the endocytic pathway, some of them being adressed to the lysosomal compartment where they are degraded. The mechanisms controling the different steps of transport and targetting of the immunoreceptors to specialized compartments of the cells have recently been adressed but are still largely unknown. This review will focus on the potential role of some signalling molecules in the endosomal transport of the immunoreceptors. Indeed, as previously discussed they all share stricking similarities in terms of structure and function and the signalling pathways triggered by antigen binding to these different receptors also present similarities. It is thus possible that some of the mechanisms controlling their transport in the endocytic pathway may be common. However, we have to keep in mind that the physiological relevances of the endocytosis and transport of the different immunoreceptors are different. For the TcR, a rapid downregulation and degradation of the triggered receptors may be crucial to turn off a T cell response. Moreover the fact that a given CD3/TCR complex can only be triggered once ensure a strict control by the number of antigenic determinants of the length and strength of T cell activation. In the case of BcR and FcRs, internalization and degradation are mainly involved in facilitating the endocytosis of soluble or complexed antigens. In both cases the receptors facilitate the access of antigens to specialized compartments where they are degraded into peptides which then associate with MHC class II molecules, thus allowing antigen presentation and immune response of T cell clones. It is thus evident that the unravelling of the mechanisms controlling endocytosis and transport of the immunoreceptors is of utmost interest in the understanding of immune response.