title: Rho kinase promotes alloimmune responses by regulating the proliferation and structure of T cells.
abstract: Coordinated rearrangements of the actin-myosin cytoskeleton facilitate early and late events in T cell activation and signal transduction. As many important features of cell shape rearrangement involve small GTP-binding proteins, we examined the contribution of Rho kinase to the functions of mature T cells. Inhibitors of the Rho kinase pathway all had similar actions to inhibit the proliferation of primary lymphocyte cultures. Likewise, transfection of the human Jurkat T cell line with a dominant negative, kinase-defective mutant of Rho kinase diminished Jurkat cell proliferation. Furthermore, inhibition of Rho kinase substantially attenuated the program of cytokine gene expression that characterizes T cell activation, blocked actomyosin polymerization, and prevented aggregation of the TCR/CD3 complex colocalized with lipid rafts. These actions are relevant to immune responses in vivo, as treatment with a Rho kinase inhibitor considerably prolonged the survival of fully allogeneic heart transplants in mice and diminished intragraft expression of cytokine mRNAs. Thus, Rho GTPases acting through Rho kinase play a unique role in T cell activation during cellular immune responses by promoting structural rearrangements that are critical for T cell signaling.
authors.affiliation: Duke University and Veterans Affairs Medical Centers, Durham, NC 27705, USA.
authors.forename: Pierre-Louis
authors.initials: PL
authors.lastname: Tharaux
authors.forename: Richard C
authors.initials: RC
authors.lastname: Bukoski
authors.forename: Paulo N
authors.initials: PN
authors.lastname: Rocha
authors.forename: Steven D
authors.initials: SD
authors.lastname: Crowley
authors.forename: Phillip
authors.initials: P
authors.lastname: Ruiz
authors.forename: Chandra
authors.initials: C
authors.lastname: Nataraj
authors.forename: David N
authors.initials: DN
authors.lastname: Howell
authors.forename: Kozo
authors.initials: K
authors.lastname: Kaibuchi
authors.forename: Robert F
authors.initials: RF
authors.lastname: Spurney
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Coffman
mesh_terms: D000199:Actins / Q000378:metabolism; D000577:Amides / Q000494:pharmacology; D000818:Animals; D017252:CD3 Complex / Q000276:immunology; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D003208:Concanavalin A / Q000494:pharmacology; D003599:Cytoskeleton / Q000276:immunology*; D004789:Enzyme Activation / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006084:Graft Rejection / Q000201:enzymology / Q000276:immunology; D006131:Growth Inhibitors / Q000494:pharmacology; D016027:Heart Transplantation / Q000276:immunology; D006801:Humans; D007106:Immune Sera / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D007519:Isoantigens / Q000276:immunology*; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008297:Male; D021962:Membrane Microdomains / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology; D013601:T-Lymphocytes / Q000166:cytology* / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D014162:Transfection; D054460:rho-Associated Kinases
chemical_list: D000199:Actins; D000577:Amides; D017252:CD3 Complex; D004791:Enzyme Inhibitors; D006131:Growth Inhibitors; D007106:Immune Sera; D047908:Intracellular Signaling Peptides and Proteins; D007519:Isoantigens; D011725:Pyridines; D003208:Concanavalin A; C108830:Y 27632; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases