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To improve characterization of human TReg cells, we compiled a unique microarray consisting of 350 TReg cell associated genes (Human TReg Chip) based on whole genome transcription data from human and mouse TReg cells. TReg cell specific gene signatures were created from 11 individual healthy donors. Statistical analysis identified 62 genes differentially expressed in TReg 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 TReg cell function were recovered. Strikingly, the vast majority of genes identified had not previously been associated with human TReg 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 TReg cell function.
Twenty-one of these 62 genes have already been described in the literature as being associated with TReg cells of both mouse and human origin, including FOXP3, CTLA4, IL2RA (CD25), and ITGB2 (Figure 3). Recovery of these 'old friends' confirmed our nonredundant microarray approach, including our cell separation strategy. Among the 62 genes, eight that were previously only implicated in murine TReg cell biology were also detected as being differentially expressed in human TReg cells (LGALS1, IL7R, GATA3, SATB1, TNFRSF1B, TNSF5, DGKA, and CCR5). Altogether, 15 genes were identified that were similarly regulated in mouse and human. Those genes at the intersection of both organisms reflect high levels of interspecies conservation during the evolutionary process, thereby lending credibility to their important role in TReg cell development and function (Figure 3). In addition to FOXP3, CTLA4 and IL2RA, we also found the chemokine receptor 7 (CCR7), the transferring receptor (TFRC) and integrin beta 2 (ITGB2) genes in this intersection group between mouse and human. Furthermore, six genes previously associated with human TReg cells were identified. Apart from the 'old friends', we identified 41 'new players' that have not previously been reported in the context of human TReg cells (Figure 3).
Old friends and new players. Genes differentially expressed in regulatory and naïve T cells, as identified by application of the Human TReg Chip. The upper half of the Venn diagram summarizes 'old friends'(namely, TReg cell associated genes that have previously been described in literature for either mouse or human). The lower half of the chart illustrates the new situation by showing all of the 'new players' of the TReg cell fingerprint. As demonstrated by the extended intersection, we identified eight genes, which formerly had only been implicated in mouse TReg cell immunology, as playing an additional role in human TRegcell activity (red arrow). Furthermore, our results expanded our knowledge on the transcriptional pattern characterizing human TReg cells by adding 41 new candidate genes (indicated by the red '+').
Old friends: confirmation of microarray results. Real-time RT-PCR was performed for (a) FOXP3, (b) CTLA4, (c) CCR7, and RPS9 (data not shown) expression in MACS separated human CD4+CD25+ TReg and CD4+CD25- naïve T cells. Following normalization to RPS9, relative mRNA amounts in CD4+CD25+ TReg cells were adjusted to corresponding expression levels in CD4+CD25- naïve T cells and expressed as fold changes. Real-time RT-PCR results, indicated by black bars, were compared with fold changes arising from the Human TReg Chip (represented by grey bars). The healthy donors, randomly chosen, are specified by letters (see Table 1). RT-PCR, reverse transcription polymerase chain reaction.
Apart from the 'old friends', our TReg cell signature comprises 41 'new players' that have not yet been described in TReg cells at all. Because TReg cells have a far-reaching effect on our health by influencing the outcome of infection, autoimmunity, transplantation, and cancer, we studied whether these new candidates have been reported to participate in these processes. Interestingly, the vast majority of the genes identified in our study (51 out of 62) have been implicated in at least one of these disease scenarios (Table 2).
This study provides new insight into gene expression characterizing human regulatory versus naïve T cells from individual healthy donors. Based on our nonredundant microarray approach, we identified a comprehensive set of 62 'old friends' and 'new players' that are differentially expressed in TReg cells. Pathway analysis implicated most of these genes in functional key modules of survival/apoptosis, TCR signaling/activation/proliferation, and differentiation/maintenance of TReg cells and might therefore represent promising new targets for therapeutic intervention. This is underlined by the fact that these genes have been widely associated with diverse clinical setting of autoimmune diseases. Functional dissection of the modules under pathophysiological conditions should help to unravel the remaining mysteries of human TReg cells and is essential for future development of new therapeutic approaches exploiting their potential in balancing peripheral tolerance. 2b1af7f3a8