title: Proteomics analysis reveals a Th17-prone cell population in presymptomatic graft-versus-host disease.
abstract: Gastrointestinal graft-versus-host-disease (GI-GVHD) is a life-threatening complication occurring after allogeneic hematopoietic cell transplantation (HCT), and a blood biomarker that permits stratification of HCT patients according to their risk of developing GI-GVHD would greatly aid treatment planning. Through in-depth, large-scale proteomic profiling of presymptomatic samples, we identified a T cell population expressing both CD146, a cell adhesion molecule, and CCR5, a chemokine receptor that is upregulated as early as 14 days after transplantation in patients who develop GI-GVHD. The CD4+CD146+CCR5+T cell population is Th17 prone and increased by ICOS stimulation. shRNA knockdown of CD146 in T cells reduced their transmigration through endothelial cells, and maraviroc, a CCR5 inhibitor, reduced chemotaxis of the CD4+CD146+CCR5+T cell population toward CCL14. Mice that received CD146 shRNA-transduced human T cells did not lose weight, showed better survival, and had fewer CD4+CD146+CCR5+T cells and less pathogenic Th17 infiltration in the intestine, even compared with mice receiving maraviroc with control shRNA- transduced human T cells. Furthermore, the frequency of CD4+CD146+CCR5+Tregs was increased in GI-GVHD patients, and these cells showed increased plasticity toward Th17 upon ICOS stimulation. Our findings can be applied to early risk stratification, as well as specific preventative therapeutic strategies following HCT.
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Liangyi
authors.initials: L
authors.lastname: Liu
authors.affiliation: University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Aurelie
authors.initials: A
authors.lastname: Gomez
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Jilu
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Abdulraouf
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authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
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authors.initials: Q
authors.lastname: Zhang
authors.affiliation: University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Sung W
authors.initials: SW
authors.lastname: Choi
authors.affiliation: University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.affiliation: University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Joel K
authors.initials: JK
authors.lastname: Greenson
authors.affiliation: Rutgers-Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.
authors.forename: Chen
authors.initials: C
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authors.affiliation: National Jewish Health, Denver, Colorado, USA.
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authors.initials: D
authors.lastname: Jiang
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Virts
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Kelich
authors.affiliation: National Jewish Health, Denver, Colorado, USA.
authors.forename: Hong Wei
authors.initials: HW
authors.lastname: Chu
authors.affiliation: University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Flynn
authors.affiliation: University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Helmut
authors.initials: H
authors.lastname: Hanenberg
authors.affiliation: MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Samir
authors.initials: S
authors.lastname: Hanash
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Sophie
authors.initials: S
authors.lastname: Paczesny