title: CRK proteins selectively regulate T cell migration into inflamed tissues.
abstract: Effector T cell migration into inflamed sites greatly exacerbates tissue destruction and disease severity in inflammatory diseases, including graft-versus-host disease (GVHD). T cell migration into such sites depends heavily on regulated adhesion and migration, but the signaling pathways that coordinate these functions downstream of chemokine receptors are largely unknown. Using conditional knockout mice, we found that T cells lacking the adaptor proteins CRK and CRK-like (CRKL) exhibit reduced integrin-dependent adhesion, chemotaxis, and diapedesis. Moreover, these two closely related proteins exhibited substantial functional redundancy, as ectopic expression of either protein rescued defects in T cells lacking both CRK and CRKL. We determined that CRK proteins coordinate with the RAP guanine nucleotide exchange factor C3G and the adhesion docking molecule CASL to activate the integrin regulatory GTPase RAP1. CRK proteins were required for effector T cell trafficking into sites of inflammation, but not for migration to lymphoid organs. In a murine bone marrow transplantation model, the differential migration of CRK/CRKL-deficient T cells resulted in efficient graft-versus-leukemia responses with minimal GVHD. Together, the results from our studies show that CRK family proteins selectively regulate T cell adhesion and migration at effector sites and suggest that these proteins have potential as therapeutic targets for preventing GVHD.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Huang
authors.forename: Fiona
authors.initials: F
authors.lastname: Clarke
authors.forename: Mobin
authors.initials: M
authors.lastname: Karimi
authors.forename: Nathan H
authors.initials: NH
authors.lastname: Roy
authors.forename: Edward K
authors.initials: EK
authors.lastname: Williamson
authors.forename: Mariko
authors.initials: M
authors.lastname: Okumura
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Mochizuki
authors.forename: Emily J H
authors.initials: EJ
authors.lastname: Chen
authors.forename: Tae-Ju
authors.initials: TJ
authors.lastname: Park
authors.forename: Gudrun F
authors.initials: GF
authors.lastname: Debes
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Tom
authors.initials: T
authors.lastname: Curran
authors.forename: Taku
authors.initials: T
authors.lastname: Kambayashi
authors.forename: Janis K
authors.initials: JK
authors.lastname: Burkhardt
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology; D000818:Animals; D016026:Bone Marrow Transplantation; D002448:Cell Adhesion; D016764:Cell Polarity; D002478:Cells, Cultured; D002633:Chemotaxis; D006086:Graft vs Host Disease / Q000276:immunology / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D008221:Lymphoid Tissue / Q000276:immunology / Q000473:pathology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000502:physiology; D050737:Proto-Oncogene Proteins c-crk / Q000502:physiology*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000502:physiology* / Q000637:transplantation; D057705:Transendothelial and Transepithelial Migration; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C082869:CRKL protein; D009687:Nuclear Proteins; D050737:Proto-Oncogene Proteins c-crk; D020830:rac1 GTP-Binding Protein