Targeting the T-cell compartment. The left panel highlights the central role of T-cell activation within SLO for GVHD initiation. APC activate and expand allo-reactive T cells, which then migrate to target organs. Secretion of pro-inflammatory cytokines, such as IFN-γ and IL-21 are hallmarks of a sustained alloreactive T-cell response. In this GVHD-favouring scenario, the balance within the T-cell compartment is on the effector T-cell side. The right panel depicts potential strategies inhibiting T-cell activation or SLO occupancy to inhibit or prevent GVHD development. Antibodies inhibiting SLO entry might help to prevent T-cell priming, whereas blockade of T-cell exit by FTY720 inhibits the migration of GVHD-mediating T cells to GVHD target organs. Other drugs help to tip the balance toward the Treg compartment, such as mTOR inhibitors, STAT1 inhibitors or antibodies blocking IL-21. The activation process of T cells can also be directly inhibited by PKC-inhibitors (eg AEB071). Compounds in clinical testing are shown in brown, promising T-cell targeting strategies to be tested in future clinical trials are given in red. TC indicates T-cell; Treg, regulatory T-cell; HEV, high endothelial venules; mTOR, mammalian target of rapamycin; mAb, monoclonal antibody; MadCAM, mucosal addressin cell adhesion molecule; and SLO, secondary lymphoid organ.