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      T Cell Costimulation by CD6 Is Dependent on Bivalent Binding of a GADS/SLP-76 Complex

      research-article
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      Molecular and Cellular Biology
      American Society for Microbiology
      CD6, GADS, SLP-76, T cells, signal transduction

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          ABSTRACT

          The cell surface receptor CD6 regulates T cell activation in both activating and inhibitory manners. The adaptor protein SLP-76 is recruited to the phosphorylated CD6 cytoplasmic Y662 residue during T cell activation, providing an activating signal to T cells. In this study, a biochemical approach identified the SH2 domain-containing adaptor protein GADS as the dominant interaction partner for the CD6 cytoplasmic Y629 residue. Functional experiments in human Jurkat and primary T cells showed that both mutations Y629F and Y662F abolished costimulation by CD6. In addition, a restraint on T cell activation by CD6 was revealed in primary T cells expressing CD6 mutated at Y629 and Y662. These data are consistent with a model in which bivalent recruitment of a GADS/SLP-76 complex is required for costimulation by CD6.

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          Most cited references33

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          The cytotoxic T cell proteome and its shaping by mammalian Target of Rapamycin

          High-resolution mass spectrometry maps the cytotoxic T lymphocyte (CTL) proteome and the impact of mammalian target of rapamycin complex 1 (mTORC1) on CTLs. The CTL proteome was dominated by metabolic regulators and granzymes and mTORC1 selectively repressed and promoted expression of subset of CTL proteins (~10%). These included key CTL effector molecules, signaling proteins and a subset of metabolic enzymes. Proteomic data highlighted the potential for mTORC1 negative control of phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3) production in CTL. mTORC1 was shown to repress PtdIns(3,4,5)P3 production and to determine the mTORC2 requirement for activation of the kinase Akt. Unbiased proteomic analysis thus provides a comprehensive understanding of CTL identity and mTORC1 control of CTL function.
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            Long-term engagement of CD6 and ALCAM is essential for T-cell proliferation induced by dendritic cells.

            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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              Oligomerization of signaling complexes by the multipoint binding of GRB2 to both LAT and SOS1.

              Receptor oligomerization is vital for activating intracellular signaling, in part by initiating events that recruit effector and adaptor proteins to sites of active signaling. Whether these distal molecules themselves oligomerize is not well appreciated. In this study, we examined the molecular interactions of the adaptor protein GRB2. In T cells, the SH2 domain of GRB2 binds phosphorylated tyrosines on the adaptor protein LAT and the GRB2 SH3 domains associate with the proline-rich regions of SOS1 and CBL. Using biochemical and biophysical techniques in conjunction with confocal microscopy, we observed that the simultaneous association of GRB2, via its SH2 and SH3 domains, with multivalent ligands led to the oligomerization of these ligands, which affected signaling. These data suggest that multipoint binding of distal adaptor proteins mediates the formation of oligomeric signaling clusters vital for intracellular signaling.
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                Author and article information

                Journal
                Mol Cell Biol
                Mol. Cell. Biol
                mcb
                mcb
                MCB
                Molecular and Cellular Biology
                American Society for Microbiology (1752 N St., N.W., Washington, DC )
                0270-7306
                1098-5549
                13 March 2017
                16 May 2017
                1 June 2017
                16 May 2017
                : 37
                : 11
                : e00071-17
                Affiliations
                Sir William Dunn School of Pathology, Oxford, United Kingdom
                Author notes
                Address correspondence to Marion H. Brown, Marion.Brown@ 123456path.ox.ac.uk .

                Citation Breuning J, Brown MH. 2017. T cell costimulation by CD6 is dependent on bivalent binding of a GADS/SLP-76 complex. Mol Cell Biol 37:e00071-17. https://doi.org/10.1128/MCB.00071-17.

                Article
                00071-17
                10.1128/MCB.00071-17
                5440646
                28289074
                3ec1d8a8-8026-437d-b038-41a7335053f8
                Copyright © 2017 Breuning and Brown.

                This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

                History
                : 16 February 2017
                : 1 March 2017
                Page count
                Figures: 7, Tables: 3, Equations: 0, References: 34, Pages: 12, Words: 6953
                Categories
                Research Article
                Spotlight
                Custom metadata
                June 2017

                Molecular biology
                cd6,gads,slp-76,t cells,signal transduction
                Molecular biology
                cd6, gads, slp-76, t cells, signal transduction

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