Introduction: Dysregulation of interleukin 6 (IL-6) is pivotal for the development of graft-versus-host-disease (GVHD), the major clinical limitation of allogeneic stem cell transplantation (allo-SCT). IL-6 drives many protective as well as inflammatory effects, the latter involving differentiation of T cells into pathogenic Th22, Th17, and Tc17 subsets. IL-6 signals through three principal pathways; classical, whereby IL-6 binds to the IL-6R-gp130 receptor complex on cellular targets, trans, utilizing the soluble IL-6R-IL-6 complex to signal to cellular gp130 alone or cluster, involving cognate presentation of the IL-6R-IL-6 by dendritic cells to gp130 on T cells. Importantly, the signalling pathways and the various cellular targets involved in the generation of pathogenic T cells during GVHD remains unclear. Since clinical IL-6 inhibitors differentially target these pathways, understanding the pathways generating pathology is critical to guide therapy.  Aims: To dissect the contribution of the IL-6 signalling pathways to T cell differentiation and GVHD. Methods: Donor bone marrow and T cells were transplanted from lineage-specific Cre x IL-6^fl/fl or IL-6R^fl/fl mice into irradiated, MHC disparate, wild-type or sgp-130:Fc transgenic recipient mice with or without IL-6R mAb. Donor T cell differentiation and GVHD was assessed after transplant. Results: Surprisingly, IL-6 trans-signalling was not required for T cell differentiation and GVHD, but instead regulated Th22 cell development. Indeed, inhibition of IL-6 trans-signalling in sgp130:Fc recipients promoted the expansion of Th22 cells and generated severe cutaneous GVHD. In contrast, IL-6 classical-signalling was critical for the development of Th22 and Th17 cells and its inhibition significantly attenuated GVHD broadly. Interestingly, unlike Th17 differentiation, Tc17 differentiation was highly IL-6-dependent but independent of classical and trans-signalling pathways, consistent with induction by cluster-signalling in isolation. Conclusion: These data highlight cluster, in addition to classical IL-6-signalling as key therapeutic targets.