title: SHP-1 Acts as a Key Regulator of Alloresponses by Modulating LFA-1-Mediated Adhesion in Primary Murine T Cells.
abstract: The clinical potential of transplantation is often reduced by T cell-mediated alloresponses that cause graft rejection or graft-versus-host disease. Integrin-mediated adhesion between alloreactive T cells and antigen-presenting cells is essential for allorejection. The identity of the signaling events needed for the activation of integrins such as LFA-1 is poorly understood. Here, we identified a novel role of the protein tyrosine phosphatase SHP-1 in the regulation of murine LFA-1-mediated adhesion in an allograft setting. Upon alloactivation, SHP-1 activity is reduced, resulting in an increase in LFA-1 adhesion compared to that for syngeneically activated T cells. The importance of these differential activation properties was further indicated by small interfering RNA (siRNA) knockdown of SHP-1 in syngeneically and allogeneically stimulated T cells. Mechanistically, SHP-1 modulated the binding of SLP-76 to ADAP by dephosphorylation of the YDGI tyrosine motif of ADAP, a known docking site for the Src family kinase Fyn. This novel key role of SHP-1 in the regulation of LFA-1-mediated adhesion may provide a new insight into T cell-mediated alloresponses and may pave the way to the development of new immunosuppressive pharmaceutical agents.
authors.affiliation: Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: Martin G
authors.initials: MG
authors.lastname: Sauer
authors.affiliation: Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: Jessica
authors.initials: J
authors.lastname: Herbst
authors.affiliation: Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany.
authors.forename: Ulf
authors.initials: U
authors.lastname: Diekmann
authors.affiliation: Cell Signalling Section, Department of Pathology, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Rudd
authors.affiliation: Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany kardinal.christian@mh-hannover.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Kardinal
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism*; D064591:Allografts / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D002448:Cell Adhesion; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D018380:Hematopoietic Stem Cell Transplantation; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism*; D051379:Mice; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C491468:Fyb protein, mouse; D016169:Lymphocyte Function-Associated Antigen-1; D010750:Phosphoproteins; C092947:SLP-76 signal Transducing adaptor proteins; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C509248:Ptpn6 protein, mouse