Reduced expression of NFAT-associated genes in UCB versus adult CD4+ T lymphocytes during primary stimulation.
The cellular and molecular mechanisms underlying the blunted allo-responsiveness of umbilical cord blood (UCB) T cells have not been fully elucidated. Protein expression of NFATc2 (nuclear factor of activated T cells c2), a critical transcription factor necessary for up-regulation of multiple cytokines known to amplify T-cell allogeneic responses, is reduced in UCB T cells. Affymetrix oligonucleotide microarrays were used to compare gene expression of primary purified CD4+ UCB T cells to adult peripheral blood CD4+ T cells (AB) at baseline, 6, and 16 hours of primary stimulation. NFAT-regulated genes exhibited lower expression in UCB CD4+ T cells including the following: granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), interleukin 3 (IL-3), IL-4, IL-5, IL-13, IL-2 receptor alpha (IL-2Ralpha; CD25), CD40L, and macrophage inflammatory protein 1 alpha (MIP-1alpha). Transcription factors involved in the NFAT pathway including C/EBPbeta, JunB, and Fosl1 (Fra-1), as well as Th1- and Th2-related transcription factors STAT4 (signal transducers and activators of transcription 4), T-bet, and c-maf showed reduced expression in UCB compared with AB during primary stimulation. Reduced cytokine, chemokine, and receptor expression was also found in UCB. Gene array data were confirmed using RNase protection assays, flow cytometry, and quantitative multiplexed cytokine measurements. Reduced global expression of NFAT-associated genes, as well as cytokines and chemokines, in UCB CD4+ T cells may contribute to the decreased graft-versus-host disease (GVHD) observed after UCB transplantation.
Kaminski
Beth A
BA
Case Western Reserve University, 11100 Euclid Ave, Wearn 433, Cleveland, OH 44106-5065, USA.
Kadereit
Suzanne
S
Miller
Robin E
RE
Leahy
Patrick
P
Stein
Kevin R
KR
Topa
David A
DA
Radivoyevitch
Tomas
T
Veigl
Martina L
ML
Laughlin
Mary J
MJ
D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D018925:Chemokines / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D036101:Cord Blood Stem Cell Transplantation; D016207:Cytokines / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D004268:DNA-Binding Proteins / Q000097:blood / Q000502:physiology*; D005312:Fetal Blood / Q000166:cytology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006086:Graft vs Host Disease / Q000235:genetics; D006801:Humans; D007231:Infant, Newborn; D008213:Lymphocyte Activation; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis / Q000097:blood / Q000235:genetics / Q000502:physiology*
D018925:Chemokines; D016207:Cytokines; D004268:DNA-Binding Proteins; D050778:NFATC Transcription Factors; C494006:NFATC2 protein, human; D009687:Nuclear Proteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D014157:Transcription Factors