Separation of graft-versus-host disease from graft-versus-leukemia responses by targeting CC-chemokine receptor 7 on donor T cells

James M. Coghill, Michael J. Carlson, Angela Panoskaltsis-Mortari, Michelle L. West, Joseph E. Burgents, Bruce R. Blazar, Jonathan S. Serody

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

CC-chemokine receptor 7 (CCR7) is expressed on the surface of naive T cells, and plays a critical role in their movement into secondary lymphoid tissue. Here, we show that murine T cells lacking CCR7 (CCR7-/-) generate attenuated graft-versus-host disease (GVHD) responses compared with wild-type (WT) cells, with the difference varying inversely with the degree of major histocompatibility complex (MHC) disparity between the donor and recipient. CCR7-/- T cells exhibited an impaired ability to traffic to recipient lymph nodes, with an increased capacity to home to the spleen. CCR7-/- T cells, however, demonstrated a reduced ability to undergo in vivo expansion in the spleen due to impaired interactions with splenic antigen-presenting cells. On a cellular level, CCR7-/- T cells were functionally competent, demonstrating a normal in vitro proliferative capacity and a preserved ability to produce inflammatory cytokines. Importantly, CCR7-/- T cells were capable of generating robust graftversus-leukemia (GVL) responses in vivo, as well as complete donor T-cell reconstitution. CCR7-/- regulatory T cells were able to protect against lethal GVHD when administered before WT conventional T cells. Our data suggest that CCR7 inhibition in the early posttransplantation period may represent a feasible new therapeutic approach for acute GVHD attenuation without compromising GVL responses.

Original languageEnglish (US)
Pages (from-to)4914-4922
Number of pages9
JournalBlood
Volume115
Issue number23
DOIs
StatePublished - Jun 10 2010

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