Journal
BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION
Volume 13, Issue 1, Pages 46-55Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.bbmt.2006.09.014
Keywords
graft-versus-host disease; interferon-gamm; allogeneic hematopoietic cell transplantation; CD8 T cells
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Funding
- NCI NIH HHS [R01 CA79989, P01 CA111519, R01 CA079989] Funding Source: Medline
- NHLBI NIH HHS [T32 HL007529] Funding Source: Medline
- NIAID NIH HHS [T32 AI007529] Funding Source: Medline
- NICHD NIH HHS [5T32 HD07529-06] Funding Source: Medline
- NIDDK NIH HHS [T32 DK007529] Funding Source: Medline
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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 VVT 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. (C) 2007 American Society for Blood and Marrow Transplantation.
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