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Prepublished online as a Blood First Edition Paper on August 28, 2003; DOI 10.1182/blood-2003-05-1732.
Submitted May 29, 2003
Accepted August 7, 2003
Reduced expression of NFAT-associated genes in UCB versus adult CD4+ T lymphocytes during primary stimulation
Beth A Kaminski, Suzanne Kadereit, Robin E Miller, Patrick Leahy, Kevin R Stein, David A Topa, Tomas Radivoyevitch, Martina L Veigl, and Mary J Laughlin*
Department of Medicine, Case Western Reserve University, Cleveland, OH, USA
Ireland Cancer Center, Case Western Reserve University, Cleveland, OH, USA
Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA
* Corresponding author; email: mjl13{at}po.cwru.edu.
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, 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: GM-CSF, IFN- , TNF- , IL-3, IL-4, IL-5, IL-13, IL-2R (CD 25), CD40L, and MIP1-. Transcription factors involved in the NFAT pathway including C/EBP , JunB, and Fosl1 (Fra-1), as well as Th1 and Th2 related transcription factors STAT4, T-bet, and c-maf showed reduced expression in UCB as compared to AB during primary stimulation. Reduced cytokine, chemokine, and receptor expression was also found in UCB. Gene array data was 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.
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