Signatures of human regulatory T cells: an encounter with old friends and new players

Background: Naturally occurring CD4(+)CD25(+) regulatory T cells (T-Reg) are involved in the control of autoimmune diseases, transplantation tolerance, and anti-tumor immunity. Thus far, genomic studies on T-Reg cells were restricted to murine systems, and requirements for their development, maintenance, and mode of action in humans are poorly defined. Results: To improve characterization of human T-Reg cells, we compiled a unique microarray consisting of 350 T-Reg cell associated genes (Human T-Reg Chip) based on whole genome transcription data from human and mouse T-Reg cells. T-Reg cell specific gene signatures were created from 11 individual healthy donors. Statistical analysis identified 62 genes differentially expressed in T-Reg cells, emphasizing some cross-species differences between mice and humans. Among them, several 'old friends' (including FOXP3, CTLA4, and CCR7) that are known to be involved in T-Reg cell function were recovered. Strikingly, the vast majority of genes identified had not previously been associated with human T-Reg cells (including LGALS3, TIAF1, and TRAF1). Most of these 'new players' however, have been described in the pathogenesis of autoimmunity. Real-time RT-PCR of selected genes validated our microarray results. Pathway analysis was applied to extract signaling modules underlying human T-Reg cell function. Conclusion: The comprehensive set of genes reported here provides a defined starting point to unravel the unique characteristics of human T-Reg cells. The Human T-Reg Chip constructed and validated here is available to the scientific community and is a useful tool with which to study the molecular mechanisms that orchestrate T-Reg cells under physiologic and diseased conditions.