CCR1/CCL5 (RANTES) receptor-ligand interactions modulate allogeneic T-cell responses and graft-versus-host disease following stem-cell transplantation.
Acute graft-versus-host disease (GVHD) and leukemic relapse are serious complications of allogeneic stem-cell transplantation (SCT). Recruitment of activated T cells to host target tissues or sites of leukemic infiltration (graft-versus-leukemia [GVL]) is likely mediated by chemokine receptor-ligand interactions. We examined the contribution of donor cell CCR1 expression to the development of GVHD and GVL using a well-established murine SCT model (B6 --> B6D2F1) and CCR1-deficient mice (CCR1(-/-)). Allo-SCT with CCR1(-/-) donor cells significantly reduced systemic and target organ GVHD severity, and CCR1 expression on both T cells and accessory cells contributed to GVHD mortality. Significant GVL activity was preserved following CCR1(-/-) SCT, but the survival advantage diminished with increasing tumor burden. We then explored the effects of CCR1 expression on allo-specific T-cell responses. Although cytolytic effector function was maintained on a per-cell basis, T-cell proliferation and IFNgamma secretion were significantly reduced both in vivo and in vitro. T-cell function was partially dependent on interactions between CCR1 and CCL5. Collectively, these data demonstrate that CCR1 expression on donor cells contributes to the development of both GVHD and GVL, and suggest that CCR1/CCL5 receptor-ligand interactions modulate allo-specific T-cell responses occurring in this context.
Choi
Sung W
SW
Department of Pediatrics, Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, MI, USA.
Hildebrandt
Gerhard C
GC
Olkiewicz
Krystyna M
KM
Hanauer
David A
DA
Chaudhary
Meghana N
MN
Silva
Ines A
IA
Rogers
Clare E
CE
Deurloo
Daphne T
DT
Fisher
Jacki M
JM
Liu
Chen
C
Adams
David
D
Chensue
Stephen W
SW
Cooke
Kenneth R
KR
D000818:Animals; D018946:Chemokine CCL5 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005786:Gene Expression Regulation; D006086:Graft vs Host Disease / Q000209:etiology / Q000235:genetics / Q000276:immunology* / Q000401:mortality; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011485:Protein Binding / Q000502:physiology; D054389:Receptors, CCR1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D033581:Stem Cell Transplantation / Q000009:adverse effects*; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014184:Transplantation, Homologous
C503460:Ccl5 protein, mouse; C515301:Ccr1 protein, mouse; D018946:Chemokine CCL5; D054389:Receptors, CCR1