IL-6 trans signaling regulates GVHD via the suppression of donor Th22 differentiation. (A-D) Lethally irradiated B6 wild-type (B6.WT) and sgp130Fc (IL-6 trans signaling inhibited) mice received 10 × 10⁶ BALB/c BM and 5 × 10⁶ T-cell allografts from WT or IL-22–deficient donors (BALB/c.IL-22^−/−). (A-C) Survival indices by Kaplan-Meier analyses (A), combined clinical scores (B), and scores of skin pathology (C) after transplantation (n = 18 mice per group from 3 experiments). (D) Representative skin sections taken at day 21 after transplantation (hematoxylin and eosin stain; 200× magnification). (E) Lethally irradiated B6D2F1 and sgp130Fc.F1 (IL-6 trans signaling inhibited) mice received BM and T-cell allografts from control mice (CD4Cre⁻ × IL-6R^fl) or mice with T cells deficient in IL-6 classical signaling (CD4Cre⁺ × IL-6R^fl) and frequency (F) and total number (G) of Th22 cells measured at day 7 after transplantation in the peripheral LNs (pLNs) (n = 8 mice per group from 2 experiments). (H-J) Recipient B6.WT and sgp130Fc (IL-6 trans signaling inhibited) mice were treated with anti–IL-6R antibody (all IL-6 signaling pathways blocked) or control immunoglobulin G (IgG) antibody and CD4⁺ T-cell differentiation assessed at day 7 after transplantation of BALB/c.WT T cells. (H-I) Representative contour plots of IL-22 and IL-17A expression in CD4⁺ T cells from the pLNs (concatenated from 4 mice per group) (H) and frequency of CD4⁺ T cells and total number of Th22 cells (I) (CD4⁺IL-22⁺IL-17A⁻; n = 8 mice per group from 2 experiments). Data presented as mean ± standard error of the mean. *P < .05, **P < .01, ***P < .001. n.s., not significant; TBI, total-body irradiation.