Reduced expression of NFAT-associated genes in UCB versus adult CD4plus 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 Tcell allogeneic responses, is reduced in UCB T cells. Affymetrix oligonucleotide microarrays were used to compare gene expression of primary purifie 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(IFN), tumor necrosis factor(TNF), interleukin 3 (IL-3), IL-4, IL-5, IL-13, IL-2 receptor (IL-2R ; CD25), CD40L, and macrophage inflammator protein 1 (MIP-1 ). Transcription factors involved in the NFAT pathway including C/EBP , JunB, and Fosl1 (Fra-1), as well as Th1and Th2related 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 confirme using RNase protection assays, flo 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. (Blood. 2003;102:4608-4617)