Pierre Bourdieu

Th1 cell differentiation involves two main signaling pathways, IL-12/STAT4 signaling and IFN-γ/STAT1 signaling, and expression of the master-regulator of Th1 cell differentiation,

the T-box binding transcription factor T-bet. T-bet upregulation as a result of T cell activation is enhanced by IFN-γ/STAT1 signaling and contributes to Th1 cell

differentiation through a number of pathways including the upregulation of IL-12Rβ2,

allowing the selective expansion of T-bet-expressing cells via APC-derived IL-12, synergizing with other transcription factors to further induce IFN-γ expression and

inhibiting IL-4 expression via binding of a silencer element within the IL-4 promoter (Amsen et al., 2009). T-bet can also negatively regulate Th2 cell differentiation through a kinase-dependent interaction with GATA3 that interferes with GATA3 DNA-binding activity (Hwang et al., 2005).

The molecular requirements for optimal Th2 cell differentiation include signaling via the IL-4/STAT6 and IL-2/STAT5 pathways and expression of the transcription factor GATA3. IL-4/STAT6 signaling in conjunction with TCR signaling results in the upregulation of GATA3 while the signaling via IL-2/STAT5 is thought to stabilize IL-4 expression and provide signals for the survival and expansion of Th2 cells. Early experiments looking for factors that drive Th2 cell differentiation identified the transcription factors NFAT, AP- 1 and c-maf as synergistically contributing to IL-4 production through consensus binding sites within the IL-4 promoter (Ho et al., 1996; Rooney et al., 1995) but GATA3 alone

appears to be capable of inducing full transactivation of the IL-4 locus, including IL-5 and IL-13 expression, and reciprocal regulation of Th1 cell differentiation through inhibition of IL-12Rβ2 expression (Amsen et al., 2009). Although use of recombinant IL-4 is the

standard for in vitro Th2 polarization, Th2 cell differentiation can occur in the absence of either IL-4 or STAT6 when complemented by enforced STAT5 signaling (Zhu et al., 2003) and previously published studies have shown that development of Th2 cells is unimpaired in vivo in the absence of either STAT6 or IL-4 during infection with

Nippostrongylus brasiliensis (van Panhuys et al., 2008). Additional pathways for the induction of Th2 cell differentiation involving Notch signaling have also been proposed and components of the Notch signaling pathway directly bind to sites within the promoter and enhancer regions of GATA3 and IL-4 respectively (Amsen et al., 2009).

Similar to natural Treg, inducible or adaptive Treg differentiation in the periphery is often associated with expression of the transcription factor, Foxp3. However in contrast to natural Treg development in the thymus, it is sub-optimal TCR stimulation together with TGF-β and IL-2 that upregulates Foxp3 expression through the respective activation of

NFAT, STAT5 and SMAD that bind to various regions of the Foxp3 promoter (Josefowicz and Rudensky, 2009). aTregs also exhibit increased expression of CD25 (IL-2Rα) and IL-2 is important in the selective expansion and survival of aTreg. Signals

from the vitamin A metabolite retinoic acid (RA) can additionally promote aTreg development and enhance TGF-β-dependent induction of Foxp3 expression. Constant

low level antigen stimulation from food products and commensal organsims coupled with the identification of CD103+ _{DCs capable of producing TGF-}

2007; Sun et al., 2007), favors the intestinal environment as a major site for peripheral aTreg induction and suggests a protective function for aTreg in suppressing inflammation at mucosal sites. However, the relative importance of natural versus aTreg

in vivo remains to be determined.

Initiation of Th17 cell differentiation is dependent on TGFβ signaling in conjunction with

IL-6-, IL-21, or IL-23-mediated STAT3 activation and expression of the transcription factor RORγt, while autocrine expression of IL-21 also serves as a positive feedback

loop re-inforcing Th17 cell induction (Korn et al., 2009). Recent work has placed the AP1 transcription factor BATF as a key player in Th17 cell induction (Schraml et al., 2009) and it is likely that BATF cooperates with factors including RORγt and IRF4

(Brustle et al., 2007) to enforce Th17 cell differentiation. The role of IL-23 in Th17 cell differentiation has remained controversial. Although in vitro studies have clearly shown that IL-23 is not required for the initiation of Th17 cell differentiation, consistent with the observation that naïve T cells do not express the IL-23R, the full and sustained differentiation and survival of Th17 cells appears to require IL-23, implicating IL-23 as a necessary feedback signal for the maintenance of Th17 cell responses in vivo (Korn et al., 2009).

Since the discovery of the requirement for TGFβ in the differentiation of Th17 cells

(Bettelli et al., 2006; Mangan et al., 2006; Veldhoen et al., 2006), it has become clear that there is a close relationship between the development of Th17 cells and aTreg cells, supported by the preferential induction of these two subsets within intestinal tissue and

the capacity of their signature transcription factors, Foxp3 and RORγt, to cross-regulate

each other through direct protein-protein interactions (Ichiyama et al., 2008; Zhou et al., 2008). Additionally, cells co-expressing Foxp3 and RORγt have been identified in the

murine small intestine that produce less IL-17 than RORγt single-expressors (Zhou et al.,

2008) and in humans, a Foxp3+_IL-17+ _{peripheral regulatory T cell population has recently}

been identified (Voo et al., 2009). These findings, taken together with a recent study demonstrating the ability of former Foxp3-expressing cells to adopt a pathogenic phenotype (Zhou et al., 2009), support a more fluid, plastic model of helper cell differentiation than originally envisaged where lineage commitment is not a terminal step and Th cells may adopt an altered phenotype based on the interpretation of external cues. Further dissection of the factors, including signals from commensal organisms, that regulate the balance between Th17 and aTreg cell differentiation in the steady state may help identify individuals with a predisposition to inflammatory disease as well as provide new therapeutic targets for treatment.