An essential role for IFN-gamma in regulation of alloreactive CD8 T cells following allogeneic hematopoietic cell transplantation.
We previously found that CD8 T cells from IFN-gamma gene knockout (GKO) donors induce more severe lethal GVHD compared with CD8 T cells from wild-type (WT) donors in fully MHC-mismatched strain combinations. In this study, we investigated the mechanisms by which IFN-gamma inhibits GVHD in a parent --> F1 (B6 --> B6D2F1) allogeneic HCT (allo-HCT) model. IFN-gamma was strongly protective against GVHD in this parent --> F1 haplotype-mismatched allo-HCT model. Irradiated B6D2F1 mice that received GKO B6 CD4-depleted splenocytes developed lethal GVHD with severe lung and liver injury, whereas those receiving a similar cell population from WT B6 donors survived long term. Donor CD8 cells showed rapid activation, accelerated cell division, and reduced/delayed activation-induced cell death in allogeneic recipients in which donor cells were incapable of producing IFN-gamma. In consequence, the numbers of activated/effector (ie, CD25+, CD62L-, and CD44(high)) donor CD8 T cells in the recipients of GKO allo-HCT significantly exceeded those in mice receiving WT allo-HCT. These data show that IFN-gamma negatively regulates the CD8 T cell response by inhibiting cell division and promoting cell death and suggest that blockade of IFN-gamma could augment the severity of GVHD in patients undergoing allo-HCT.
Asavaroengchai
Wannee
W
Bone Marrow Transplantation Section, Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02129, USA.
Wang
Hui
H
Wang
Shumei
S
Wang
Lan
L
Bronson
Roderick
R
Sykes
Megan
M
Yang
Yong-Guang
YG
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation; D007371:Interferon-gamma / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens / Q000276:immunology; D023421:Models, Animal; D014184:Transplantation, Homologous
D015778:Minor Histocompatibility Antigens; D007371:Interferon-gamma