An activated Th17-prone T cell subset involved in chronic graft-versus-host 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. Serody & 7 others John Koreth, Corey S. Cutler, Joseph H. Antin, Robert J. Soiffer, Jerome Ritz, Sophie Paczesny, Bruce R Blazar

Research output: Contribution to journalArticle

17 Citations (Scopus)

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)
JournalJCI insight
Volume2
Issue number12
DOIs
StatePublished - Jun 15 2017

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T-Lymphocyte Subsets
Graft vs Host Disease
Pharmacology
T-Lymphocytes
Interleukin-17
Bronchiolitis Obliterans
Lung
Blocking Antibodies
Germinal Center
Alveolar Macrophages
Stem Cell Transplantation
Helper-Inducer T-Lymphocytes
Cell Movement
Flow Cytometry
B-Lymphocytes
Biomarkers
Tissue Donors

Keywords

  • Immunology
  • Transplantation

Cite this

An activated Th17-prone T cell subset involved in chronic graft-versus-host disease sensitive to pharmacological inhibition. / Forcade, Edouard; Paz, Katelyn; Flynn, Ryan; Griesenauer, Brad; Amet, Tohti; Li, Wei; Liu, Liangyi; Bakoyannis, Giorgos; Jiang, Di; Chu, Hong Wei; Lobera, Mercedes; Yang, Jianfei; Wilkes, David S.; Du, Jing; Gartlan, Kate; Hill, Geoffrey R.; MacDonald, Kelli Pa; Espada, Eduardo L.; Blanco, Patrick; Serody, Jonathan S.; Koreth, John; Cutler, Corey S.; Antin, Joseph H.; Soiffer, Robert J.; Ritz, Jerome; Paczesny, Sophie; Blazar, Bruce R.

In: JCI insight, Vol. 2, No. 12, 15.06.2017.

Research output: Contribution to journalArticle

Forcade, E, Paz, K, Flynn, R, Griesenauer, B, Amet, T, Li, W, Liu, L, Bakoyannis, G, Jiang, D, Chu, HW, Lobera, M, Yang, J, Wilkes, DS, Du, J, Gartlan, K, Hill, GR, MacDonald, KP, Espada, EL, Blanco, P, Serody, JS, Koreth, J, Cutler, CS, Antin, JH, Soiffer, RJ, Ritz, J, Paczesny, S & Blazar, BR 2017, 'An activated Th17-prone T cell subset involved in chronic graft-versus-host disease sensitive to pharmacological inhibition', JCI insight, vol. 2, no. 12. https://doi.org/10.1172/jci.insight.92111
Forcade, Edouard ; Paz, Katelyn ; Flynn, Ryan ; Griesenauer, Brad ; Amet, Tohti ; Li, Wei ; Liu, Liangyi ; Bakoyannis, Giorgos ; Jiang, Di ; Chu, Hong Wei ; Lobera, Mercedes ; Yang, Jianfei ; Wilkes, David S. ; Du, Jing ; Gartlan, Kate ; Hill, Geoffrey R. ; MacDonald, Kelli Pa ; Espada, Eduardo L. ; Blanco, Patrick ; Serody, Jonathan S. ; Koreth, John ; Cutler, Corey S. ; Antin, Joseph H. ; Soiffer, Robert J. ; Ritz, Jerome ; Paczesny, Sophie ; Blazar, Bruce R. / An activated Th17-prone T cell subset involved in chronic graft-versus-host disease sensitive to pharmacological inhibition. In: JCI insight. 2017 ; Vol. 2, No. 12.
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AU - Forcade, Edouard

AU - Paz, Katelyn

AU - Flynn, Ryan

AU - Griesenauer, Brad

AU - Amet, Tohti

AU - Li, Wei

AU - Liu, Liangyi

AU - Bakoyannis, Giorgos

AU - Jiang, Di

AU - Chu, Hong Wei

AU - Lobera, Mercedes

AU - Yang, Jianfei

AU - Wilkes, David S.

AU - Du, Jing

AU - Gartlan, Kate

AU - Hill, Geoffrey R.

AU - MacDonald, Kelli Pa

AU - Espada, Eduardo L.

AU - Blanco, Patrick

AU - Serody, Jonathan S.

AU - Koreth, John

AU - Cutler, Corey S.

AU - Antin, Joseph H.

AU - Soiffer, Robert J.

AU - Ritz, Jerome

AU - Paczesny, Sophie

AU - Blazar, Bruce R

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