Graft-versus-host disease (GVHD) is a major complication of allogenic bone marrow transplantation and involves the infiltration of donor CD4(+) and/or CD8(+) T cells into various organs of the recipient. The pathological role of human CD4(+) and CD8(+) T cells in GVHD remains controversial. In this study, we established two novel xenogeneic (xeno)-GVHD models. Human CD4(+) or CD8(+) T cells were purified from peripheral blood and were transplanted into immunodeficient NOD/Shi-scid IL2rg(null) (NOG) mice. Human CD8(+) T cells did not induce major GVHD symptoms in conventional NOG mice. However, CD8(+) T cells immediately proliferated and induced severe GVHD when transferred into NOG mice together with at least 0.5 x 10(6) CD4(+) T cells or into NOG human interleukin (IL)-2 transgenic mice. Human CD4(+) T cell-transplanted NOG mice developed skin inflammations including alopecia, epidermal hyperplasia, and neutrophilia. Pathogenic T helper (Th)17 cells accumulated in the skin of CD4(+) T cell-transplanted NOG mice. Further, an anti-human IL-17 antibody (secukinumab) significantly suppressed these skin pathologies. These results indicate that pathogenic human Th17 cells induce cutaneous GVHD via IL-17-dependent pathways. This study provides fundamental insights into the pathogenesis of xeno-GVHD, and these humanized mouse models may be useful as preclinical tools for the prevention of GVHD. Human CD4(+) or CD8(+) T cells contribute differently to the pathogenesis of xenogenic graft-versus-host disease.