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

Kate H Gartlan, Kate A Markey, Antiopi Varelias, Mark D Bunting, Motoko Koyama, Rachel D Kuns, Neil C Raffelt, Stuart D Olver, Katie E Lineburg, Melody Cheong, Bianca E Teal, Mary Lor, Iain Comerford, Michele W L Teng, Mark J Smyth, James McCluskey, Jamie Rossjohn, Brigitta Stockinger, Glen M Boyle, Steven W Lane, Andrew D Clouston, Shaun R McColl, Kelli P A MacDonald, Geoffrey R Hill

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-DC together with IL-6. Tc17 cells express high levels of multiple prototypic lineage-defining transcription factors (e.g. RORγt, T-bet) and cytokines (e.g. IL-17A, IL-22, IFNγ, GM-CSF, IL-13). Targeted depletion of Tc17 early after transplant protects from lethal acute GVHD, however Tc17 cells are non-cytolytic and fail to mediate graft-versus-leukemia (GVL) effects. Thus, the Tc17 differentiation program during GVHD culminates in a highly plastic, hyper-inflammatory, poorly-cytolytic effector population which we term inflammatory Tc17 (iTc17). Since iTc17 mediate GVHD without contributing to GVL, therapeutic inhibition of iTc17 development in a clinical setting represents an attractive approach for separating GVHD and GVL.