Reduced NFAT1 protein expression in human umbilical cord blood T lymphocytes.
Umbilical cord blood (UCB) stem cells from related and unrelated allogeneic donors have emerged as novel treatment for patients with hematologic malignancies. The incidence and severity of acute graft-versus-host disease (GVHD) after UCB transplantation compares favorably with that observed in recipients of matched unrelated donor allogeneic grafts, but remains a major cause of morbidity and mortality. It has been shown that stimulated lymphocytes from UCB have reduced production of cytokines including interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha), which play a role in GVHD pathophysiology. We investigated the molecular mechanisms underlying this reduced cytokine production by analyzing expression of nuclear factor of activated T cells-1 (NFAT1) in UCB T cells. We detected no constitutive expression of NFAT1 protein in unstimulated UCB T cells compared with adult T cells. Moreover, although NFAT1 expression in UCB T cells was upregulated after prolonged (40 hours) T-cell stimulation, it was only partially upregulated when compared with adult controls. Our observation of minimal NFAT1 expression after stimulation correlated with reduced cytoplasmic IFN-gamma and TNF-alpha production in UCB T cells studied simultaneously. Reduced NFAT1 expression may blunt amplification of donor UCB T-cell alloresponsiveness against recipient antigens, thereby potentially limiting GVHD incidence and severity after allogeneic UCB transplantation.
Kadereit
S
S
University Hospitals Ireland Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106-5065, USA.
Mohammad
S F
SF
Miller
R E
RE
Woods
K D
KD
Listrom
C D
CD
McKinnon
K
K
Alali
A
A
Bos
L S
LS
Iacobucci
M L
ML
Sramkoski
M R
MR
Jacobberger
J W
JW
Laughlin
M J
MJ
D000328:Adult; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D005312:Fetal Blood; D005434:Flow Cytometry; D006801:Humans; D008213:Lymphocyte Activation; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D013601:T-Lymphocytes / Q000378:metabolism*; D014157:Transcription Factors / Q000096:biosynthesis*; D015854:Up-Regulation
D004268:DNA-Binding Proteins; D050778:NFATC Transcription Factors; C494006:NFATC2 protein, human; D009687:Nuclear Proteins; D014157:Transcription Factors