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Tc17 cells are a proinflammatory, plastic lineage of pathogenic CD8+ T cells that induce GVHD without antileukemic effects

Gartlan, K. H., Markey, K. A., Varelias, A., Bunting, M. D., Koyama, M., Kuns, R. D., Raffelt, N. C., Olver, S. D., Lineburg, K. E., Cheong, M., Teal, B. E., Lor, M., Comerford, I., Teng, M. W. L., Smyth, M. J., McCluskey, J., Rossjohn, Jamie, Stockinger, B., Boyle, G. M., Lane, S. W., Clouston, A. D., McColl, S. R., MacDonald, K. P. A. and Hill, G. R. 2015. Tc17 cells are a proinflammatory, plastic lineage of pathogenic CD8+ T cells that induce GVHD without antileukemic effects. Blood 126 (13) , pp. 1609-1620. 10.1182/blood-2015-01-622662

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Abstract

IL-17–producing cells are important mediators of graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (SCT). Here we demonstrate that a distinct CD8+ Tc17 population develops rapidly after SCT but fails to maintain lineage fidelity such that they are unrecognizable in the absence of a fate reporter. Tc17 differentiation is dependent on alloantigen presentation by host dendritic cells (DCs) together with IL-6. Tc17 cells express high levels of multiple prototypic lineage-defining transcription factors (eg, RORγt, T-bet) and cytokines (eg, IL-17A, IL-22, interferon-γ, granulocyte macrophage colony-stimulating factor, IL-13). Targeted depletion of Tc17 early after transplant protects from lethal acute GVHD; however, Tc17 cells are noncytolytic and fail to mediate graft-versus-leukemia (GVL) effects. Thus, the Tc17 differentiation program during GVHD culminates in a highly plastic, hyperinflammatory, poorly cytolytic effector population, which we term “inflammatory iTc17” (iTc17). Because iTc17 cells mediate GVHD without contributing to GVL, therapeutic inhibition of iTc17 development in a clinical setting represents an attractive approach for separating GVHD and GVL.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Publisher: American Society of Hematology
ISSN: 0006-4971
Date of Acceptance: 9 July 2015
Last Modified: 11 Jun 2019 12:53
URI: http://orca-mwe.cf.ac.uk/id/eprint/84818

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