A master transcriptional regulator of human Th9 cells still awaits identification, and even FoxP3, which delineates murine Treg cells, is not exclusively specific for human Treg cells, since it can be upregulated upon polyclonal TCR activation alone [15]. Epigenetics determines the cell-type-specific status of the chromatin landscape. Epigenetic modifications, Selleckchem EPZ6438 especially histone modifications and DNA methylation, have been shown to regulate gene accessibility and thus help establish gene expression programs. Inclusion of epigenetics in defining Th subsets allows for better specification

of these subsets, and in particular, offers an approximation of their degree of flexibility [16, 17]. Nevertheless, recently a new concept emerged

for the specification of Th-cell identity which takes regulatory elements of the genome into consideration. Enhancers are extragenic DNA sequences that mediate the combinatorial recruitment of transcription factors to “enhance” transcription of cognate target genes [18]. They are the accessible part of a cell’s genome and are hypersensitive to digestion by DNaseI. New technologies such as genome-wide microarrays and high-throughput sequencing have contributed to establish enhancer landscapes for certain Th-cell subsets (reviewed in [19]). BMN 673 ic50 Interestingly, Protein kinase N1 several independent studies demonstrated that these enhancer landscapes determine Th-cell identity irrespective of the putative master transcriptional regulators because the enhancer landscapes of Th1, Th17, and Treg cells were not affected following the deletion of Tbet, ROR-γt, and FoxP3, respectively [20-22]. TCR-dependent signals have been shown to generate the initial phase of the enhancer landscape, which is then followed by modification of cytokine signaling in a STAT-dependent manner. For example,

many differentially active enhancers in Th1 and Th2 and Th17 cells have been shown to be STAT4, STAT6, or STAT3 dependent, respectively [20-22]. Master transcriptional regulators therefore rather seem to fine-tune Th-cell functions, while the enhancer landscape sets the tone in response to environmental signals such as microbe-elicited cytokine milieus. The expression of certain chemokine receptors has significantly contributed to the categorization of Th-cell subsets in humans [23]. The circulating immunological T-cell memory compartment is generally divided into effector memory (TEM) and central memory (TCM) subsets. TEM cells circulate to nonlymphoid tissues whereas TCM cells home to secondary lymphoid organs.