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
previously 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 in cytokine profile. 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
regardless of ongoing IL-17A expression 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.