Long-term engagement of CD6 and ALCAM is essential for T-cell proliferation induced by dendritic cells

Stanford University, Palo Alto, California, United States
Blood (Impact Factor: 10.45). 05/2006; 107(8):3212-20. DOI: 10.1182/blood-2005-09-3881
Source: PubMed


Interactions between T cells and antigen-presenting cells (APCs) are the first step in the induction of an adaptive immune response. Here, we show that CD6 and its ligand activated leukocyte cell adhesion molecule (ALCAM) are actively recruited to the antigen-induced dendritic cell (DC)-T-cell contact zone. Moreover, ALCAM-blocking antibodies interfere with DC-T-cell conjugate formation, demonstrating that CD6-ALCAM binding is essential for stable T-cell-APC contact. We now demonstrate that besides their role in establishing initial contacts, CD6-ALCAM interactions are also required during the proliferative phase of the T-cell response; the presence of CD6-blocking antibodies or recombinant ALCAM-Fc proteins results in a strong and sustained inhibition of T-cell proliferation. Furthermore, simultaneous crosslinking of CD6 and CD3 induces enhanced proliferation and transcriptional activity to a similar level as observed after CD3 and CD28 co-crosslinking, demonstrating that CD6 is an important costimulatory molecule. The stability of ALCAM-CD6 binding, which contrasts with transient homotypic ALCAM-ALCAM interactions, further supports the long-lasting effects observed on T-cell proliferation. Taken together, we demonstrate that CD6 and ALCAM form a key adhesive receptor-ligand pair that is not only involved in early DC-T-cell binding but also in sustaining DC-induced T-cell proliferation long after the initial contact has been established.

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    • "Topology of CD6/CD166 Interactions On engagement by CD166, CD6 has been observed to move into areas of close contact between T cells and antigen-presenting cells (Castro et al., 2007; Gimferrer et al., 2004; Zimmerman et al., 2006), suggesting that the interacting receptors will match the dimensions of the T-cell receptor and other receptors observed to colocalize, $140 A ˚ (Dushek et al., 2012) (Figure 2). The nonlinear domain structure may be important for accommodating CD6 in areas of close apposition between cells. "
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    ABSTRACT: CD6 is a transmembrane protein with an extracellular region containing three scavenger receptor cysteine rich (SRCR) domains. The membrane proximal domain of CD6 binds the N-terminal immunoglobulin superfamily (IgSF) domain of another cell surface receptor, CD166, which also engages in homophilic interactions. CD6 expression is mainly restricted to T cells, and the interaction between CD6 and CD166 regulates T-cell activation. We have solved the X-ray crystal structures of the three SRCR domains of CD6 and two N-terminal domains of CD166. This first structure of consecutive SRCR domains reveals a nonlinear organization. We characterized the binding sites on CD6 and CD166 and showed that a SNP in CD6 causes glycosylation that hinders the CD6/CD166 interaction. Native mass spectrometry analysis showed that there is competition between the heterophilic and homophilic interactions. These data give insight into how interactions of consecutive SRCR domains are perturbed by SNPs and potential therapeutic reagents. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.
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    • "Little is known about the function of these sCD5 and sCD6 forms. However, in vitro studies have demonstrated that affinity-purified recombinant forms of these molecules selectively inhibit T-cell proliferation induced by certain polyclonal stimuli and antigen-presenting cells [13] [14] [15]). "
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    • "The interaction of CD6 with CD166/ALCAM has been extensively mapped [8] and is known to occur through the interaction of the most membrane-proximal domain (SRCR3) of CD6 with the most N-terminal Ig domain (D1) of CD166/ALCAM. This interaction is critical in different physiological situations involving cell-to-cell contact, such as developing thymocytes binding to TEC [27] [43], and APC-mediated T-cell proliferation [13] [47]. These processes should from now on be considered susceptible of regulation by galectins via interaction with either CD6 or CD166/ALCAM. "
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    ABSTRACT: CD6 is a lymphocyte glycoprotein receptor that physically associates with the antigen-specific receptor complex at the center of the immunological synapse, where it interacts with its ligand CD166/ALCAM. The present work reports the carbohydrate-dependent interaction of CD6 and CD166/ALCAM with Galectin-1 and -3, two well-known soluble mammalian lectins. Both galectins interfered with superantigen-induced T cell proliferation and cell adhesion phenomena mediated by the CD6-CD166/ALCAM pair, while CD6 expression protected cells from galectin-induced apoptosis. The results suggest that interaction of Galectin-1 and -3 with CD6 and CD166/ALCAM might modulate some relevant aspects of T cell physiology.
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