Proteomics analysis reveals a Th17-prone cell population in presymptomatic graft-versus-host disease
Wei Li, … , Samir Hanash, Sophie Paczesny
Wei Li, … , Samir Hanash, Sophie Paczesny
Published May 5, 2016
Citation Information: JCI Insight. 2016;1(6):e86660. https://doi.org/10.1172/jci.insight.86660.
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Categories: 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 1

A CD4+CD146+CCR5+ T cell population in allogeneic HCT patients at GVHD onset and prior to GVHD onset.

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A CD4+CD146+CCR5+ T cell population in allogeneic HCT patients at GVHD o...
(A) Representative plots showing CCR5 and CD146 expression in samples from patients with GI-GVHD, without GVHD, with non-GVHD enteritis, and with skin GVHD. (B) CD4+CD146+CCR5+ T cell frequencies in healthy donors (HD), autotransplant patients (Auto), and allogeneic patients. n and median post-HCT onset of signs or samples are shown below the graphs. The data are shown as mean ± SEM, 2-tailed Student’s t tests. (C) Six-month nonrelapse mortality since sample draw in allogeneic HCT patients with symptoms (GI-GVHD, non-GVHD enteritis, and skin GVHD, n = 166) divided by low and high CD146+CCR5+ T cell frequencies. High-risk group in red (CD4+CD146+CCR5+ T cell frequency ≥ 2.3%, n = 51) and low-risk group in blue (CD146+CD146+CCR5+ T cell frequency < 2.3%, n = 115), P = 0.001, calculated for the overall curve. (D) Six-month relapse mortality since sample draw in the same population, P = 0.64. (E) Six-month event-free survival since sample draw in the same population, P = 0.002. (F) CD4+CD146+CCR5+ T cell frequency in paired samples prior to GVHD onset in GI-GVHD patients (n = 31) with a median interval of 14 days between the first measurement and measurement at onset of disease and at matched time points in non-GVHD enteritis patients (n = 7), paired t test analysis. Cumulative incidence (C and D) and Kaplan-Meier analysis (E) used.