An inflammatory checkpoint regulates recruitment of graft-versus-host reactive T cells to peripheral tissues.
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.
Chakraverty
Ronjon
R
Transplantation Biology Research Center, Bone Marrow Transplantation Section, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA.
Côté
Daniel
D
Buchli
Jennifer
J
Cotter
Pete
P
Hsu
Richard
R
Zhao
Guiling
G
Sachs
Teviah
T
Pitsillides
Costas M
CM
Bronson
Roderick
R
Means
Terry
T
Lin
Charles
C
Sykes
Megan
M
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D045142:Cross-Priming / Q000276:immunology; D006086:Graft vs Host Disease / Q000276:immunology; D006087:Graft vs Host Reaction / Q000276:immunology*; D007249:Inflammation / Q000276:immunology*; D051379:Mice; D011828:Radiation Chimera / Q000276:immunology; D012867:Skin / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D051193:Toll-Like Receptors / Q000378:metabolism
D051193:Toll-Like Receptors