An activated Th17-prone T cell subset involved in chronic graft-versushost disease sensitive to pharmacological inhibition

Edouard Forcade, Katelyn Paz, Ryan Flynn, Brad Griesenauer, Tohti Amet, Wei Li, Liangyi Liu, Giorgos Bakoyannis, Di Jiang, Hong Wei Chu, Mercedes Lobera, Jianfei Yang, David S. Wilkes, Jing Du, Kate Gartlan, Geoffrey R. Hill, Kelli Pa MacDonald, Eduardo L. Espada, Patrick Blanco, Jonathan S. SerodyJohn Koreth, Corey S. Cutler, Joseph H. Antin, Robert J. Soiffer, Jerome Ritz, Sophie Paczesny, Bruce R Blazar

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

Chronic graft-versus-host disease (cGvHD) remains a major complication of allogeneic stem cell transplantation requiring novel therapies. CD146 and CCR5 are expressed by activated T cells and associated with increased T cell migration capacity and Th17 polarization. We performed a multiparametric flow cytometry analysis in a cohort of 40 HSCT patients together with a cGvHD murine model to understand the role of CD146-expressing subsets. We observed an increased frequency of CD146+ CD4 T cells in the 20 patients with active cGvHD with enhanced RORγt expression. This Th17-prone subset was enriched for cells coexpressing CD146 and CCR5 that harbor mixed Th1/Th17 features and were more frequent in cGvHD patients. Utilizing a murine cGvHD model with bronchiolitis obliterans (BO), we observed that donor T cells from CD146-deficient mice versus those from WT mice caused significantly reduced pulmonary cGvHD. Reduced cGvHD was not the result of failed germinal center B cell or T follicular helper cell generation. Instead, CD146-deficient T cells had significantly lower pulmonary macrophage infiltration and T cell CCR5, IL-17, and IFN-γ coexpression, suggesting defective pulmonary end-organ effector mechanisms. We, thus, evaluated the effect of TMP778, a small-molecule RORγt activity inhibitor. TMP778 markedly alleviated cGvHD in murine models similarly to agents targeting the Th17 pathway, such as STAT3 inhibitor or IL-17–blocking antibody. Our data suggest CD146-expressing T cells as a cGvHD biomarker and suggest that targeting the Th17 pathway may represent a promising therapy for cGvHD.

Original languageEnglish (US)
Article numbere92111
JournalJCI Insight
Volume2
Issue number12
DOIs
StatePublished - Jun 15 2017

Bibliographical note

Funding Information:
This work was supported by the NIH (R01 CA168814, R01 CA183559, R01 CA183560, P01 CA142106, P01 AI056299), the Leukemia & Lymphoma Society Scholar Award (1293-15), the Lilly Physician Scientist Initiative Award, Cancer Biology Training grant T32 CA009138, the Ted and Eileen Pasquarello Research Fund, the MD-PhD program (University Hospital of Bordeaux, France), and the French Society of Hematology (SFH) and Association Laurette Fugain. Immunofluorescence imaging was provided by the University of Minnesota - University Imaging Centers, http://uic.umn.edu.

Publisher Copyright:
© 2017 American Society for Clinical Investigation. All rights reserved.

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