STAT-3 and ERK 1/2 phosphorylation are critical for T-cell alloactivation and graft-versus-host disease.
Graft-versus-host disease (GVHD) is a serious complication of allogeneic bone marrow transplantation, and donor T cells are indispensable for GVHD. Current therapies have limited efficacy, selectivity, and high toxicities. We used a novel flow cytometry technique for the analysis of intracellular phosphorylation events in single cells in murine BMT models to identify and validate novel GVHD drug targets.(1-7) This method circumvents the requirement for large numbers of purified cells, unlike western blots. We defined a signaling profile for alloactivated T cells in vivo and identified the phosphorylation of ERK1/2 and STAT-3 as important events during T-cell (allo)activation in GVHD. We establish that interference with STAT-3 phosphorylation can inhibit T-cell activation and proliferation in vitro and GVHD in vivo. This suggests that phospho-specific flow cytometry is useful for the identification of promising drug targets, and ERK1/2 and STAT-3 phosphorylation in alloactivated T cells may be important for GVHD.
Lu
Sydney X
SX
Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Alpdogan
Onder
O
Lin
Janine
J
Balderas
Robert
R
Campos-Gonzalez
Roberto
R
Wang
Xiao
X
Gao
Guo-Jian
GJ
Suh
David
D
King
Christopher
C
Chow
Melanie
M
Smith
Odette M
OM
Hubbard
Vanessa M
VM
Bautista
Johanne L
JL
Cabrera-Perez
Javier
J
Zakrzewski
Johannes L
JL
Kochman
Adam A
AA
Chow
Andrew
A
Altan-Bonnet
Gregoire
G
van den Brink
Marcel R M
MR
D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology*; D005434:Flow Cytometry; D006086:Graft vs Host Disease; D008213:Lymphocyte Activation; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D010766:Phosphorylation / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology*; D014184:Transplantation, Homologous
D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D048052:Mitogen-Activated Protein Kinase 3