Year: 2007
Type: article
Abstract: Our understanding of the molecular events that occur when surface receptors are engaged by their ligands has increased greatly in recent years. As signaling pathways have been defined, it has become clear that rather than occurring as a linear series of events connecting the cell surface to the nucleus, receptor-initiated second messenger cascades intersect at many points within the cell. Work in immune cells investigating the molecular interplay between immunoreceptors and integrins demonstrates well this complexity of signaling. This volume of Immunological Reviews provides articles by leading investigators interested in antigen receptors or integrins, or both, and provides new insights into how signaling events are coordinated as immune cells develop and respond to pathogenic challenges. It is well established that triggering of immunoreceptors, for example the clonotypic T-cell antigen receptor (TCR) and B-cell antigen receptor (BCR), promotes the activation of integrins, thereby inducing adhesion of lymphocytes to proteins of the extracellular matrix or to ligands on other cell types [e.g. antigen-presenting cells (APCs) or endothelial cells lining vessels]. This process, known as inside-out signaling, has been a focus of intense research for a long time. Studies have provided important insights into how one receptor system can ‘talk’ to another at the molecular level. However, it also becoming evident that the composition of the signaling complexes that regulate inside-out signals vary from cell type to cell type and also from stimulus to stimulus. Hence, there are still many issues that need to be addressed. Questions also remain concerning how integrins themselves initiate signaling events (so-called outside-in signaling) to regulate such complicated cellular processes as adhesion, migration, and diapedesis. Recent data suggest that outside-in signaling by integrins may also rely on components of other cell surface receptors, including the immunoreceptors themselves. Our view of how antigen receptors and integrins interact during cell–cell contact has changed in recent years. Originally, it was thought that integrins make the first contact between a lymphocyte and an APC and that only later antigen receptors became active. However, now it is clear that these two receptors interact closely at the early stage of lymphocyte activation by colocalizing in microclusters where the signaling occurs before a synapse between two cells is formed. It thus became clear that the interactions of these two proteins are much more dynamic than those previously appreciated. In this volume, we have brought together leading specialists in the field of immunoreceptor and integrin signaling to provide readers with a comprehensive overview of the current state of the art regarding this exciting field of research and, further, to discuss emerging questions that await answers. The first three articles concentrate on the composition and function of membrane proximal signaling complexes in hematopoietic lineages. Bezman and Koretzky (1) focus on the signaling functions of the adapter proteins linker for activated T cells (LAT) and Src homology 2 (SH2) domain-containing leukocyte phosphoprotein of 76 kDa (SLP76). In their review, they point out that LAT and SLP76 exert essential signaling functions not only in T cells but also in other hematopoietic cell types. While these adapters appear to be important for both immunoreceptor and integrin responses, these authors point out that there are interesting differences between the requirements of LAT versus SLP76 downstream of the two receptor systems. These differences appear to involve differences in subcellular distribution and/or spatiotemporal assemblies of signalosomes nucleated by the two adapters. Abram and Lowell (2) focus on the interrelationship between signaling pathways initiated by immunoreceptors versus integrins. In this article, the authors describe overlapping roles of the immunoreceptor-tyrosine-based activation motif (ITAM)-containing adapters FcRγ and DAP12 and Syk kinases in signaling by the two classes of receptors. The authors not only describe positive regulatory signals generated by immunoreceptors and integrins but also illuminate negative regulatory signaling components (e.g. Csk and tyrosine phosphatases). Besides obvious similarities, there are also notable differences between integrin and immunoreceptor signaling, such as the requirement for the adapter protein LAT. Finally, the authors mention additional signaling pathways that have adopted molecules involved in immunoreceptor-mediated signaling. The article by Gomez-Rodriguez et al. (3) discusses the role of the Tec family of non-receptor protein tyrosine kinases Itk, Rlk, and Tec during the development and activation of T and B lymphocytes. Tec kinases modify immunoreceptor-mediated signals, and in addition to their recognized roles in phospholipase Cγ (PLCγ) regulation, these kinases are involved in reorganization of the actin cytoskeleton, recruitment of signaling molecules to the immunological synapse (IS), and integrin clustering downstream of the TCR or chemokine receptors. A major focus of this review relates to the connection between Tec kinases and the guanine nucleotide exchange factor Vav1 and Cbl-b. The roles of Tec kinases in signaling downstream of chemokine receptors and hence in regulating migration and homing of lymphocytes are also outlined. Burbach et al. (4) and Ménaschéet al. (5) concentrate more specifically on the molecular cross talk between the TCR and the integrins. Burbach et al. (4) discuss current knowledge on the signaling molecules that are involved in TCR-mediated inside-out signaling and propose a four-step model for integrin activation. One additional focus of this review relates to the function of the protein kinase C effector protein kinase D, which interacts with the small guanosine triphosphatase (GTPase) Rap1 and apparently regulates the membrane localization of Rap1. The regulation of TCR-mediated inside-out signaling by Rap1 is also the major topic of the article provided by Ménaschéet al. (5). This article addresses the question of how two cytosolic adapter proteins, adhesion- and degranulation-promoting adapter protein (FrDAP) and Src kinase-associated phosphoprotein of 55 kDa (SKAP55), regulate membrane targeting of Rap1 after TCR stimulation. Both reviews discuss the roles of two recently identified Rap1 effector molecules, regulator of adhesion and cell polarization enriched in lymphoid tissues (RAPL), and Rap1–GTP-interacting adapter molecule (RIAM). Rap1 and other small GTPases represent the focus of four articles contributed by the Boss (6), Kolanus (7), Philips (8), and Ginsberg (9) laboratories. Scheele et al. (6) describe new assays allowing the functional analysis of small GTPases and further discuss their roles in hematopoietic cells. Kolanus (7) provides an overview on the cytohesin protein family, an exciting group of guanine nucleotide exchange factors for adenosine diphosphate-ribosylation factor GTPases. Cytohesins have emerged as important regulators of signal transduction in vertebrate and invertebrate biology. Kolanus discusses that cytohesin-3 is an essential component of insulin signal transduction in Drosophila as well as in human and murine liver cells, whereas cytohesin-1 is another protein that is involved in inside-out signaling, leading to the activation of β2-integrins after stimulation of the TCR or chemokine receptors in immune cells. Mor et al. (8) review the role of the β2-integrin leukocyte-function-associated antigen-1 (LFA-1) in both inside-out and outside-in signaling. One focus of this review relates to Rap1 and its central role in LFA-1 signaling. The article also describes TCR-independent signaling pathways that trigger Rap1 activation and thereby facilitating LFA-1-mediated adhesion. A model is proposed in which activation of Rap1 may lead to distinct (and partially opposing) functional outcomes, dependent on its subcellular localization. Rose et al. (9) also discuss the role of Rap1, in this case in chemokine-mediated activation of integrins, and highlight the roles of the Rap1 effector molecules RAPL and RIAM. The authors describe the interesting finding that RIAM recruits talin to the integrin β-subunit, whereas the activation of LFA-1 by RAPL involves the α-subunit tail of LFA-1. Hence, it appears as if the Rap1–RIAM and Rap1–RAPL modules likely activate integrins through distinct mechanisms. A second focus of the Rose et al. (9) review deals with outside-in signaling and integrin-mediated activation of the small GTPase Rac1. Rac1 has emerged as a key signaling molecule controlling cell motility on adhesive substrata. The authors describe the mechanisms through which α4β1 regulates Rac activation and the linkage of the α4 chain to the cytoskeleton by paxillin and talin. The role of LFA-1 in regulating T-cell migration is the major topic of the article provided by Smith et al. (10). The authors report that LFA-1 functions not only as an adhesion receptor in T cells but also as a regulator of T-cell migration. They point out that LFA-1 is organized into at least three different regions of activity in migrating cells, which may cooperate to regulate T-cell migration. The use of conformation-specific anti-LFA-1 monoclonal antibodies suggests that LFA-1 at the leading edge is found in an intermediate affinity conformation, whereas the mid-cell zone contains high-affinity LFA-1. The authors suggest that the mid-cell zone provides firm adhesion and stability and supports the cell’s leading edge to scan the environment. The uropod is reported to contain high levels of LFA-1 of unknown activity status. The article points out that not only the expression of integrins but also their ability to convert between conformations with different affinities are important. Barreiro et al. (11) provide a comprehensive overview on the role of integrins and their ligands during leukocyte migration and immune cell interactions. The authors pay special attention on the spatiotemporal regulation of cellular adhesion. Chemokine- and ligand-mediated functional effects as well as the role of proteins associated with the actin cytoskeleton and membrane microdomains in regulating adhesiveness are discussed. The authors also describe molecules that are involved in integrin signaling and that regulate dynamic processes during leukocyte migration and IS formation. The molecular dynamics and the function of the IS in T-cell activation play the central role in the article provided by Reichardt et al. (12). The authors discuss the diversity of IS structures and the duration of IS formation induced by dendritic cells versus naive B cells. They further report that short-living, highly dynamic IS and serial short contacts characterize the interaction between dendritic cells and antigen-specific T cells. In contrast, the classical long-lasting and ‘bull’s eye’-shaped IS characterizes the interaction between naive B cells and T cells. Because B cells lack expression of one negative regulator of integrin function, cytohesin interacting protein (CYTIP), the authors argue that lack of CYTIP expression might be one reason for the sustained interactions between B and T cells. The differentiation signals emerging from the different contacts are considered, focusing also on the consequences of costimulation by CD28, cytotoxic T lymphocyte antigen-4 (CTLA-4), and LFA-1. Recent data indicate that the long-lasting contacts between naive B cells and T cells result in the generation of regulatory T cells, whereas the dynamic interaction between dendritic cells and T cells induces T-cell activation. The article by Vestweber (13) discusses how signals provided by the endothelium regulate trafficking of leukocytes through the vessel wall, a process known as diapedesis. The question addressed is whether leukocytes move through the contacts that form between individual endothelial cells (the so-called junctional pathway) or directly through the endothelial cell body (the so-called transcellular pathway). Vestweber further describes the current knowledge about the adhesive and signaling function of molecules involved in diapedesis. Finally, he proposes a model in which three distinct mechanisms, mediated through the endothelial receptors VE cadherin, endothelial cell-selective adhesion molecule, and junctional adhesion molecule-C, may regulate the opening of endothelial junctions during diapedesis. Three articles within this issue of Immunological Reviews are specifically related to signaling processes in B lymphocytes. It is believed that B cells are mainly activated by soluble antigens because in vitro B-cell activation can be achieved by soluble intact ligands. In their review, Batista et al. (14) challenge this view and propose that the majority of antigens that activate B cells in vivo (e.g. in lymph nodes) are indeed tethered to the surface of APCs, either by complement or by Fc receptors. The review updates concepts related to antigen recognition by B cells, discrimination by affinity, coreceptor engagement, activation, and acquisition of antigens bound to membranes. Furthermore, the role of integrins and integrin-mediated signaling for B-cell responses is discussed, as well as possible techniques to visualize B-cell responses in vivo. One classical paradigm in T- and B-cell immunology is that signaling through immunoreceptors is mediated by ITAMs and that tonic signaling through ITAMs is required for both lymphocyte development and survival. Grande et al. (15) point out that ITAMs are not unique to immunoreceptors but also found in several cytoplasmic and viral proteins. Curiously, viral proteins containing ITAMs utilize the same signaling machinery as immunoreceptors and quite often induce malignant transformation of the host cells. However, because most, if not all ITAM-containing viral proteins, fail to induce cellular transformation in hematopoietic cells, Grande et al. propose that ITAM-containing viral proteins may initiate transformation in non-hematopoietic tissues by evading the normal counterregulation of ITAM signaling mediated through hematopoietic cell-restricted expression of negative coreceptor proteins. An important signaling event in antigen-stimulated B cells is the mobilization of the intracellular second messenger Ca2+. Engelke et al. (16) review molecular details of the early and late phases of the Ca2+ initiation process. Following ITAM phosphorylation of the BCR signaling subunits immunoglobulin (Ig)α and Igβ, a Ca2+ initiation complex comprising the adapter protein SLP-65, the Tec family kinase Burton’s tyrosine kinase (Btk), and the lipase PLCγ2 is assembled and targeted to the plasma membrane. This complex triggers Ca2+ fluxes from intra- and extracellular sources. The two distinct phases of Ca2+ mobilization are differentially regulated during B-cell maturation and correlate with diverse cellular outcomes such as clonal expansion, activation, or apoptosis. The authors provide an overview on molecules that positively and negatively regulate Ca2+ flux at different stages of B-cell differentiation and discuss how ion channels of the endoplasmic reticulum and plasma membrane facilitate Ca2+ fluxes to activate downstream targets such as activation of the transcription factors nuclear factor-κB and nuclear factor for activated T cells. The final review, provided by Kasirer-Friede et al. (17), highlights our current understanding of the structure of platelet integrins αIIbβ3, αVβ3, α2β1, α5β1, and α6β1 and the signaling mechanisms they utilize to modulate platelet function. Immunoreceptors may positively or negatively modulate integrins both at the level of inside-out and outside-in signaling. The known ITAM- and ITIM-containing immunoreceptors expressed by platelets are described, and novel interactions between integrins and immunoreceptors are discussed. Recent X-ray crystallography and electron cryomicroscopy data have indicated that large conformational changes occur during integrin activation, similarly to talin-head-induced splaying of integrin cytoplasmic tails. Kasirer-Friede et al. further propose that Rap1 and RIAM act together with talin to mediate this effect. While this collection of articles describing the molecular and functional interactions between immunoreceptors and integrins reflects a great deal of new work that has been accomplished over the past several years, it is clear that the findings presented in this volume represent only the beginnings of an appreciation for the complex cross talk between receptor systems. It can be anticipated that the next several years will bring further refinement in our knowledge of how immunoreceptors and integrins signal using both unique and interdependent pathways. It can also be anticipated that the current and future work in this area will be generalizable to other receptor pathways, important for both immune and non-immune cell function.
Source: Immunological Reviews
Authors: Burkhart Schraven, Michael Reth
Language: English
Subfield: Immunology and Allergy
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W1990436609