In vitro Th17-polarized human CD4+ T cells exacerbate xenogeneic graft-versus-host disease

Abstract 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 debated. 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-2Rγnull (NSG) mice. Naive human CD4 + T cells were stimulated under Th17-skewing conditions for 8-10 days before being co-injected in NSG mice with fresh PBMCs from the same donor. We observed that Th17-polarized cells engrafted and migrated towards xGVHD-target organs. They also acquired a double expressing IL-17A + IFNγ + profile in vivo . Importantly, we observed that co-transfer of Th17-polarized cells (1 × 10 6 ) with PBMCs (1 × 10 6 ) exacerbated xGVHD in comparison with transplantation of PBMCs alone (2 × 10 6 ). Further, PBMC co-transfer with Th17-polarized cells was more potent than co-transfer with naive CD4 + T cells stimulated in nonpolarizing conditions (Th0 cells, 1 × 10 6  + 1 × 10 6 PBMCs) or with Th1-polarized cells (1 × 10 6  + 1 × 10 6 PBMCs) for xGVHD induction. In summary, our results suggest that human Th17-polarized cells can cooperate with PBMCs and be pathogenic in the NSG xGVHD model.