STAT-3 and ERK 1/2 phosphorylation are critical for T-cell alloactivation and graft-versus-host disease

Author:

Lu Sydney X.1,Alpdogan Onder1,Lin Janine1,Balderas Robert2,Campos-Gonzalez Roberto2,Wang Xiao2,Gao Guo-Jian2,Suh David1,King Christopher1,Chow Melanie1,Smith Odette M.1,Hubbard Vanessa M.13,Bautista Johanne L.1,Cabrera-Perez Javier1,Zakrzewski Johannes L.1,Kochman Adam A.1,Chow Andrew1,Altan-Bonnet Gregoire14,van den Brink Marcel R. M.1

Affiliation:

1. Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, NY;

2. BD Biosciences, San Diego, CA;

3. Department of Pathology, Albert Einstein College of Medicine, New York, NY; and

4. Department of Computational Biology, Memorial Sloan-Kettering Cancer Center, New York, NY

Abstract

Abstract 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.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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