An inflammatory checkpoint regulates recruitment of graft-versus-host reactive T cells to peripheral tissues

• DOI: 10.1084/jem.20060376
• Publication Date: 2006-08-02T07:47:53Z
• Authors: Ronjon Chakraverty; Daniel Côté; Jennifer Buchli; Pete Cotter; Richard Hsu; Guiling Zhao; Teviah Sachs; Costas M. Pitsill...; Roderick Bronson; Terry Means; Charles Lin; Megan Sykes
• Keywords: 0301 basic medicine; T-Lymphocytes; T cells; Graft vs Host Disease; CD8-Positive T-Lymphocytes; ALLOGENEIC CHIMERAS; Graft versus host disease; DENDRITIC CELLS; Medical and Health Sciences; TARGET ORGANS; Animal tissue; ANTIGEN-PRESENTING CELLS; Graft vs Host Reaction; Mice; 03 medical and health sciences; Cross-Priming; TOTAL-BODY IRRADIATION; Animals; AUTOIMMUNE-DISEASE; IN-VIVO; TUMOR-NECROSIS-FACTOR; Skin; Inflammation; CUTTING EDGE; graft versus host reaction; Toll-Like Receptors; Basic Medicine; Articles; BONE-MARROW-TRANSPLANTATION; Radiation Chimera; Animal experimentation

Transfer of T cells to freshly irradiated allogeneic recipients leads to their rapid recruitment to nonlymphoid tissues, where they induce graft-versus-host disease (GVHD). In contrast, when donor T cells are transferred to established mixed chimeras (MCs), GVHD is not induced despite a robust graft-versus-host (GVH) reaction that eliminates normal and malignant host hematopoietic cells. We demonstrate here that donor GVH-reactive T cells transferred to MCs or freshly irradiated mice undergo similar expansion and activation, with similar up-regulation of homing molecules required for entry to nonlymphoid tissues. Using dynamic two-photon in vivo microscopy, we show that these activated T cells do not enter GVHD target tissues in established MCs, contrary to the dogma that activated T cells inevitably traffic to nonlymphoid tissues. Instead, we show that the presence of inflammation within a nonlymphoid tissue is a prerequisite for the trafficking of activated T cells to that site. Our studies help to explain the paradox whereby GVH-reactive T cells can mediate graft-versus-leukemia responses without inducing GVHD in established MCs.