Proteomics analysis reveals a Th17-prone cell population in presymptomatic graft-versus-host disease
Wei Li, Liangyi Liu, Aurelie Gomez, Jilu Zhang, Abdulraouf Ramadan, Qing Zhang, Sung W. Choi, Peng Zhang, Joel K. Greenson, Chen Liu, Di Jiang, Elizabeth Virts, Stephanie L. Kelich, Hong Wei Chu, Ryan Flynn, Bruce R. Blazar, Helmut Hanenberg, Samir Hanash, Sophie Paczesny
Wei Li, Liangyi Liu, Aurelie Gomez, Jilu Zhang, Abdulraouf Ramadan, Qing Zhang, Sung W. Choi, Peng Zhang, Joel K. Greenson, Chen Liu, Di Jiang, Elizabeth Virts, Stephanie L. Kelich, Hong Wei Chu, Ryan Flynn, Bruce R. Blazar, Helmut Hanenberg, Samir Hanash, Sophie Paczesny
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Research Article Immunology Transplantation

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

Wei Li, Liangyi Liu, Aurelie Gomez, Jilu Zhang, Abdulraouf Ramadan, Qing Zhang, Sung W. Choi, Peng Zhang, Joel K. Greenson, Chen Liu, Di Jiang, Elizabeth Virts, Stephanie L. Kelich, Hong Wei Chu, Ryan Flynn, Bruce R. Blazar, Helmut Hanenberg, Samir Hanash, Sophie Paczesny

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Figure 4

Donor human T cells with CD146 knockdown in a xenogeneic GVHD model.

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Donor human T cells with CD146 knockdown in a xenogeneic GVHD model. (A)...
(A) Body weight loss of NSG mice transplanted with lentivirally transduced human CD4+ T cells. Control shRNA group (n = 8) and CD146 shRNA group (n = 9), 2-tailed Student’s t test. (B) Kaplan-Meier survival curves. Control shRNA group (n = 30) and CD146 shRNA group (n = 27), log-rank test. (C) Human CD4+ T cell engraftment in spleen, (D) CD4+CD146+CCR5+ T cell frequency in the gut, and (E) Th17 cells coexpressing IL-17 and IFN-γ in the spleen. Mice were analyzed between days 30–45 after transplantation for C–E. Representative flow cytometric plots at the top and dot plots showing mean ± SEM values at the bottom, 2-tailed Student’s t test. The data in C and D were from 10 mice per group. The data in E were from 5 mice in the control group and 4 mice in the CD146 group. (F) Body weight loss and (G) survival curves of NSG mice transplanted with CD146 shRNA or control shRNA lentivirus and treated with maraviroc (MV) or vesicle control, 2-tailed Student’s t test for weight loss between control shRNA vs. control shRNA + MV and log-rank test for survival (n = 12 per group). (H) Human T cell infiltration in the gut of mice receiving transduced CD4+ T cells and MV or vehicle control. Mice were analyzed at day +35 after transplantation (n = 5 per group), 2-tailed Student’s t test. *P < 0.05, **P < 0.01, ***P < 0.001.