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General Discussion UvA-DARE (Digital Academic Repository) EGF-TM7 receptors: A diverse and still evolving family of receptors on the leukocyte surface Matmati, M. Publication date 2008 Link to publication Citation for published version (APA): Matmati, M. (2008). EGF-TM7 receptors: A diverse and still evolving family of receptors on the leukocyte surface. General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl) Download date:23 Sep 2021 Chapter 6 General Discussion GENERAL DISCUSSION Since their identification, starting about 15 years ago, a growing amount of data has accumulated about the structure, the expression, the ligands and, more recently, also the functional implications of EGF-TM7 receptors. Studies with antibody treatment and gene targeting in mice and antibody treatment of human cells in vitro, led to the implication of EGF-TM7 receptors in the trafficking of granulocytes, the generation of efferent antigen specific regulatory T cells and the potentiation of different granulocyte effector functions [1-4]. Nevertheless, the molecular and cellular mechanisms underpinning the role of EGF-TM7 receptors in these functions are still unknown. I here propose and discuss involvement of EGF-TM7 receptors in (the modulation of) leukocyte function through cell-cell and/or cell-extracellular matrix (ECM) interactions. This hypothesis is exemplified for the EMR3 and CD97 receptors. Moreover, I discuss some possibilities of initiation of cell signaling through the EGF-TM7 receptors as a basis for future research. EGF-TM7 receptors as molecules involved in cell-cell and cell-matrix interactions The members of the EGF-TM7 family are primarily expressed on leukocytes. We showed that EMR3 expression is restricted to myeloid cells and correlates with the maturation stage of granulocytes and monocytes (chapter 2). Interestingly, EMR3 coated beads have been shown to bind to activated neutrophils and moncocyte-derived macrophages but not to lymphocytes nor resting neutrophils [5]. Together, this suggests that EMR3 plays a role in the effector function(s) of granulocytes and monocytes. More specifically, the receptor could be involved in the cross-talk between myeloid cells during an inflammatory process. EMR3 might in this case contribute to the modulation of the cellular activity of mature granulocytes and mature moncoytes. Regarding this, it is important to know that binding of the 2A1 monoclonal antibody (mAb) to EMR2 on activated neutrophils potentiates a number of effector functions of these cells as adhesion and migration, superoxide production and proteolytic enzyme degranulation [4]. As EMR2 is highly homologous to EMR3 in its transmembrane region (chapter 4), one might speculate that similar signaling pathways may be induced by EMR3 after interaction with its respective ligand on neighboring cells. Nevertheless, ligation studies 107 with the EMR3 specific 3D7 mAb, have up till now failed to show any effect on neutrophil function (data not shown). Not only EMR3 but also EMR2 and CD97 have been shown to bind cell-surface ligands [5-7]. CD97 binds to CD55, which is ubiquitously expressed on the cell surface [8]. The affinity of the binding correlates inversely with the number of EGF-like domains of the respective CD97 isoforms [9]. In general, the interaction between CD97 and CD55 is characterized by a low affinity (86 µM for the smallest isofom) and a high off-rate (at least 0.6 s-1) [10]. This could be in line with a mechanism where CD97 mediate transient cellular interactions. This also means that with higher CD97 expression there will be a higher accumulative effect of these transient CD97-CD55 interactions in time. Interestingly, -subunit of CD97 has recently been shown to mediate co-stimulation of activated T cells through CD55 on these cells, while blocking mAbs to CD97 on antigen-specific T cell clones or to CD55 on antigen- pulsed monocytes inhibited the prol"- T cell co-cultures [11;12]. In light of this all, it is intriguing to see that T and NK cells with different functional characteristics differ significantly in their expression of CD97 (chapter 3). Moreover, it is known that antigen presenting cells (APCs) like monocytes and dendritic cells constitutively express CD97 (chapter 1). Consequently, it is tempting to speculate that the difference in CD97 expression between the T and NK cell subsets might result in differences in intensity of the CD97-CD55 mediated cross-talk between these T and NK cell subsets and APCs respectively. For NK cells we showed that the CD56bright subset has a significant higher surface expression of CD97 than its CD56dim counterpart (chapter 3). A couple of years ago, Dalbeth and co-workers demonstrated that CD56bright NK cells + monocytes in autologous NK-monocyte co-cultures compared to CD56dim NK cells [13]. Moreover, preventing cell contact between CD56bright NK cells and monocytes diminished the capacity of these levels. So in line with the above mentioned hypothesis, it would be interesting to assess the role of CD97 in the NK cell contact- CD97 would be a key player in this process, this might also explain the difference in cell contact mediated monocyte activation between CD56bright and CD56dim cells. For T cell subsets the situation is less clear. At one hand, we showed a significant difference in CD97 expression between CD4+ naive and memory cells, which might argue for a possible contribution of CD97 to the difference in activation kinetics of these subsets 108 when interacting with APCs. On the other hand, we did not see this difference when comparing naïve and memory CD8+ T cells (chapter 3). Furthermore, CD97 was readily up-regulated on all cells within 2 h of activation and with longer activation CD97 expression reached comparable levels on all subsets. With respect to the fast up- regulation of CD97 after activation of T cells, it is intriguing to know that the formation of a stable immunological synapse between DCs and T cells results from a dynamic process where DCs have to preactivate the T cells [14]. The activated T cells in turn drive the cytoskeletal polarization of the DCs, and the length of the DC-T cell contact is dependent on the activation status of the latter cells. The assembly of the DC-T cell contact is not dependent on CD28 and only partially depends on CD40L on T cells [14]. The CD97 KO mouse generated in our group would be an interesting model to approach the possible role of CD97 on T cells in the formation of DC (and other APC)- T cell contacts and the reciprocal modulation of the interacting cells. As already mentioned, CD55 is ubiquitously expressed on a diverse range of cell types and in different body compartments. Moreover, chondroitin sulfate B, which is a specific ligand for the largest isoforms of CD97 and EMR2, is expressed as a side chain of a wide variety of secreted and cell-surface proteoglycans [7;15-17]. Additionally, CD55 is up-regulated on different cell types in inflammatory conditions [18-20] while chondroitin sulfate B has been implicated in the inflammatory process in rheumatoid arthritis and multiple sclerosis and has been characterized as the major component of wound fluid in general [17;21;22]. Taken together, this indicates that cell-cell contacts mediated by EGF-TM7 receptors during inflammation might not be restricted to contacts between leukocytes alone. A possible contribution of CD97 (and EMR2) in the cross talk of (activated) leukocytes with endothelial cells, fibroblasts or synoviocytes cannot be excluded. And, as chondroitin sulfate B is a major side chain of extracellular matrix proteins [15;17], it is probable that (activated) leukocytes interact via the largest isoforms of CD97 and EMR2 with the extracellular matrix (ECM). These cell-cell contacts and/or interactions with components of the ECM might account for the role of CD97 in granulocyte migration for instance, as shown in different mouse models of inflammation [1;3;23]. Comparison of activated wild-type and CD97 knock-out granulocytes pre-incubated with activated wild-type fibroblasts/endothelial cells or chondroitin sulfate B-containing ECM proteoglycans followed by migration assays, might shed some light on if and how such CD97-mediated interactions impact on granulocyte migration. Consequently, this could lead to the unraveling of the cellular 109 and molecular mechanisms underpinning the role of CD97 in granulocyte migration in the above mentioned mouse models. Initiation of signal transduction by EGF-TM7 receptors Up till now, no initiation of signal transduction cascades through EGF-TM7 receptors has been demonstrated. This connects to the fact that it is still unclear how EGF-TM7 receptors are activated. Overexpression of the smallest and the largest isoform of human CD97 in CHO cells did not activate reporter constructs responding to NF-B and AP-1, respectively [24]. Addition of recombinant CD55 or CD97-specific mAbs did also not result in any effect. Several explanations are possible: (1) CD97 is not directly activated by ligation of the extracellular subunit. Rather this interaction facilitates binding of the TM7 region of CD97 to another (as yet unkown) ligand, inducing activation.
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