CCR2 is required for CD8-induced graft-versus-host disease.
Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (HSCT). Migration of donor-derived T cells into GVHD target organs plays a critical role in the development of GVHD and chemokines and their receptors are important molecules involved in this process. Here, we demonstrate in murine bone marrow transplantation models that the expression of the inflammatory CC chemokine receptor 2 (CCR2) on donor-derived CD8+ T cells is relevant for the control of CD8+ T-cell migration and development of GVHD. Recipients of CCR2-deficient (CCR2-/-) CD8+ T cells developed less damage of gut and liver than recipients of wild-type CD8+ T cells, which correlated with a reduction in overall GVHD morbidity and mortality. Assessment of donor CD8+ T-cell target organ infiltration revealed that CCR2-/- CD8+ T cells have an intrinsic migratory defect to the gut and liver. Other causes for the reduction in GVHD could be excluded, as alloreactive proliferation, activation, IFN-gamma production and cytotoxicity of CCR2-/- CD8+ T cells were intact. Interestingly, the graft-versus-tumor effect mediated by CCR2-/- CD8+ T cells was preserved, which suggests that interference with T-cell migration by blockade of CCR2 signaling can separate GVHD from GVT activity.
Terwey
Theis H
TH
Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, Kettering 406D, Mailbox 111, 1275 York Ave, New York, NY 10021, USA.
Kim
Theo D
TD
Kochman
Adam A
AA
Hubbard
Vanessa M
VM
Lu
Sydney
S
Zakrzewski
Johannes L
JL
Ramirez-Montagut
Teresa
T
Eng
Jeffrey M
JM
Muriglan
Stephanie J
SJ
Heller
Glenn
G
Murphy
George F
GF
Liu
Chen
C
Budak-Alpdogan
Tulin
T
Alpdogan
Onder
O
van den Brink
Marcel R M
MR
D000818:Animals; D016827:CD8 Antigens / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000166:cytology; D008099:Liver / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010198:Pancytopenia / Q000378:metabolism; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015996:Survival Rate; D013950:Thymus Gland / Q000378:metabolism
D016827:CD8 Antigens; C515335:Ccr2 protein, mouse; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D007371:Interferon-gamma