[PMC free article] [PubMed] [Google Scholar] 16. The family of Th subsets has expanded during the past two decades, and currently includes regulatory T cells (Treg), Th17, Tfh, Th9, and Th22 cells. These subsets are largely defined by the cytokines that each subset expresses, except FoxP3+ thymus-derived Tregs and T follicular helper (Tfh) cells. Thymus-derived Tregs are defined by the expression of the transcription factor FoxP3 and their suppressive functions. Tfh cells are often defined by the combination of markers (such as CXCR5, ICOS, PD-1, and Bcl-6) and their follicular localization in vivo, although they function by secreting IL-21 and IL-4 (and IL-10 in some cases) [1]. Studies with in vivo mouse models have significantly contributed to understand the developmental mechanism of each Th subsets. However, significant differences have been introduced in the immune system of humans and mice during more than 60 million years of independent evolution, and conclusions demonstrated in mouse studies are sometimes not fully translated to humans [2]. In the context of Th differentiation, it is becoming clear that the developmental mechanism is not fully shared between mice and humans in Rabbit Polyclonal to BST2 certain subsets. In this review, we will summarize the current knowledge on the cytokine conditions promoting the development of each Th subset in humans. We classify the Th subsets into two Stearoylethanolamide groups according to the similarities in the developmental mechanism between mice and humans: one with large similarities (Th1, Th2, Th9, and Th22) and the other with some differences (induced Treg, Th17, and Tfh). Then we will discuss how cytokines regulate Th differentiation programs in humans. Th subsets with similar developmental mechanisms between mice and humans Th1 IL-12 was discovered in the early 90s to play the major role for the generation of Th1 cells in both mice and humans [3,4]. In 1995, STAT4 was identified as the major transcription factor mediating the IL-12 signals, and in 2000, the transcription factor T-bet was discovered to be essential for Th1 development [5]. IFN- also contributes to the expression of IFN- and T-bet via STAT1 activation [5]. These major pathways associated with the generation of Th1 cells are largely shared between mice and humans. For example, Th1 generation is severely impaired in subjects who lack the expression of functional IL-12 and/or IL-12 receptor, due to mutations of (encoding IL-12p40 subunit common to IL-12 and IL-23), (encoding the 1 chain for the receptors of IL-12 and IL-23), (associated with the development of IL-12-producing dendritic cells (DCs)), and (a molecule that acts in synergy with IL-12) [6]. Th2 In early 90s, IL-4 was discovered as critical cytokines for the generation Stearoylethanolamide of Th2 cells in vitro in mice. STAT6 was identified as the main transcription factors downstream of IL-4 signals in 1996, and the transcription factor Gata3 was discovered to be essential for in vivo Th2 development in 1997 [7]. In addition to the IL-4-STAT6, low signals via T cell receptor (TCR) were found to play an important role for the initial expression of Gata3 in activated CD4+ T cells [8]. These mechanisms associated with Th2 development are also largely shared between mice and humans [9]. A recent study identified a set of candidate transcription factors associated with the generation of human Th2 cells through genome-wide profiling of histone modifications in human blood CCR4+ CD4+ T cells (that are enriched with Th2 cells) [10]. The set of the identified transcription factors contains Gata3 and Stat5, but also includes many transcription factors previously not implicated in Th2 cell differentiation. Whether and how these newly identified transcription factors contribute to Th2 cell differentiation in humans and/or mice remain to be determined. It is still possible that eventually the transcriptional network regulating Th2 cell differentiation turns out to be somewhat different between mice and humans. Th9 Early studies performed in the 90s demonstrated that IL-9 secretion was largely Stearoylethanolamide associated with Th2 cells [11]. However, it was also shown that the cytokine combination of IL-4, TGF-, and IL-2 can induce na?ve CD4+ T cells in vitro to.