Therapeutic deletion of IL-17 producing CD8+ T cells (Tc17) attenuates GVHD without impairing GVL. (#295)
Donor T cell polarization is a critical factor influencing the severity and tissue distribution of graft-versus-host disease (GVHD) and the potency of graft-versus-leukemia (GVL) effects after bone marrow transplantation. We have recently reported that G-CSF treatment promotes type-17 differentiation in both CD4 and CD8 T cells and that donor IL-17A, predominantly from CD8 T cells (Tc17), mediates fibrotic skin pathology manifesting late after transplant as scleroderma. To study Tc17 development and function we utilized the IL-17ACreRosa26ReYFP ‘fate-mapping’ reporter mouse and observed that donor Tc17 cells differentiate early post allogeneic transplant and transition rapidly towards a Tc1-like phenotype. Tc17 differentiation is dependent upon IL-6, host-DC and is regulated by the presence of IFNγ. Tc17 cells appear highly inflammatory, displaying considerable promiscuity in their transcriptional profile and inflammatory cytokine production. Furthermore, targeted deletion of Tc17 early post transplant was protective in a lethal model of acute GVHD. In contrast, Tc17 express only low levels of the CTL effector molecule Granzyme B and display strikingly poor GVL activity in vivo. These data demonstrate that Tc17 differentiation is an early and highly plastic differentiation program, culminating in a poorly-cytolytic, inflammatory population that mediates GVHD without contributing to GVL. Thus, early therapeutic targeting of Tc17 development via IL-6 inhibition represents a highly attractive avenue for GVHD prevention.