In Vitro Th17-Polarized Human CD4+ T Cells Exacerbate Xenogeneic Graft-versus-Host Disease

Acute graft-versus-host disease (aGVHD) is a severe complication of allogeneic hematopoietic stem cell transplantation. The role of Th17 cells in its pathophysiology remains a matter of debate. In this study, we assessed whether enrichment of human peripheral blood mononuclear cells (PBMCs) with in vitro Th17-polarized CD4(+) T cells would exacerbate xenogeneic GVHD (xGVHD) into NOD-scid IL-2R gamma null (NSG) mice. Naive human CD4(+) T cells were stimulated under Th17-skewing conditions for 8 to 10 days and then coinjected in NSG mice with fresh PBMCs from the same donor. We observed that Th17-polarized cells engrafted and migrated toward xGVHD target organs. They also acquired a double-expressing IL-17A(+)IFN gamma(+) profile in vivo. Importantly, cotransfer of Th17-polarized cells (1 x 10(6)) with PBMCs (1 x 10(6)) exacerbated xGVHD compared with transplantation of PBMCs alone (2 x 10(6)). Furthermore, PBMC cotransfer with Th17-polarized cells was more potent for xGVHD induction than cotransfer with naive CD4(+) T cells stimulated in nonpolarizing conditions (Th0 cells, 1 x 10(6) + 1 x 10(6) PBMCs) or with Thl-polarized cells (1 x 10(6) + 1 x 10(6) PBMCs). In summary, our results suggest that human Th17-polarized cells can cooperate with PBMCs and be pathogenic in the NSG xGVHD model. (C) 2018 American Society for Blood and Marrow Transplantation.