CC chemokine receptor 2 expression in donor cells serves an essential role in graft-versus-host-disease.
The complete repertoire of cellular and molecular determinants that influence graft-vs-host disease (GVHD) is not known. Using a well-established murine model of GVHD (B6-->bm12 mice), we sought to elucidate the role of the donor non-T cell compartment and molecular determinants therein in the pathogenesis of GVHD. In this model the acute GVHD-inducing effects of purified B6 wild-type (wt) CD4(+) T cells was inhibited by wt non-T cells in a dose-dependent manner. Paradoxically, unlike the chronic GVHD phenotype observed in bm12 mice transplanted with B6wt unfractionated splenocytes, bm12 recipients of B6ccr2-null unfractionated splenocytes developed acute GVHD and died of IFN-gamma-mediated bone marrow aplasia. This switch from chronic to acute GVHD was associated with increased target organ infiltration of activated CD4(+) T cells as well as enhanced expression of Th1/Th2 cytokines, chemokines, and the antiapoptotic factor bfl1. In vitro, ccr2(-/-) CD4(+) T cells in unfractionated splenocytes underwent significantly less activation-induced cell death than B6wt CD4(+) T cells, providing another potential mechanistic basis along with enhanced expression of bfl1 for the increased numbers of activated T cells in target organs of B6ccr2(-/-) splenocyte-->bm12 mice. Collectively, these findings have important clinical implications, as they implicate the donor non-T cell compartment as a critical regulator of GVHD and suggest that ccr2 expression in this cellular compartment may be an important molecular determinant of activation-induced cell death and GVHD pathogenesis.
South Texas Veterans Health Care System, Audie L. Murphy Division, San Antonio, TX 78284, USA.
Arun R
AR
Rao
Marlon P
MP
Quinones
Edgar
E
Garavito
Yogeshwar
Y
Kalkonde
Fabio
F
Jimenez
Caroline
C
Gibbons
Jennifer
J
Perez
Peter
P
Melby
William
W
Kuziel
Robert L
RL
Reddick
Sunil K
SK
Ahuja
Seema S
SS
Ahuja
D000208:Acute Disease; D000741:Anemia, Aplastic / Q000235:genetics / Q000276:immunology / Q000401:mortality / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000637:transplantation; D002469:Cell Separation; D002478:Cells, Cultured; D018925:Chemokines / Q000096:biosynthesis; D002908:Chronic Disease; D016207:Cytokines / Q000096:biosynthesis; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D006085:Graft Survival / Q000235:genetics / Q000276:immunology; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000502:physiology; D008213:Lymphocyte Activation / Q000235:genetics; D017710:Lymphocyte Transfusion / Q000401:mortality; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013154:Spleen / Q000166:cytology / Q000378:metabolism / Q000473:pathology / Q000637:transplantation
C515335:Ccr2 protein, mouse; D018925:Chemokines; D016207:Cytokines; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D007371:Interferon-gamma