Rho kinase promotes alloimmune responses by regulating the proliferation and structure of T cells.
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.
Tharaux
Pierre-Louis
PL
Duke University and Veterans Affairs Medical Centers, Durham, NC 27705, USA.
Bukoski
Richard C
RC
Rocha
Paulo N
PN
Crowley
Steven D
SD
Ruiz
Phillip
P
Nataraj
Chandra
C
Howell
David N
DN
Kaibuchi
Kozo
K
Spurney
Robert F
RF
Coffman
Thomas M
TM
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
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