Review
T helper cell differentiation: on again, off again

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Abstract

Recent studies raise the possibility that T helper (Th) polarization may be attributable to generalized activation and regulated silencing rather than regulated activation of target cytokine genes. The binding of transcription factors GATA-3 or T-bet to specific enhancers does recruit transcription factors such as NFAT-1 to IL-4 or IFNγ promoters, respectively; however, GATA-3 also intrinsically suppresses T-bet and vice versa. Silencing of GATA-3/T-bet, which is influenced by factors such as cytokines, is associated with irreversible Th polarization. For the first few divisions (perhaps reflecting the situation in lymph nodes), naive Th cells retain pluripotency; after further cell divisions (perhaps under the influence of an inflammatory cytokine milieu) they may become polarized appropriately to respond to the specific environment.

Introduction

Mechanisms by which naive CD4+ T cells achieve their effector fates continue to provide provocative twists of much interest to the understanding of immunity and broader issues of cell differentiation. Emphasis remains focused on the differentiation of naive cells to committed Th (T helper)1 and Th2 cells, which secrete the canonical cytokines IFNγ and IL-4, respectively. Observationally, Th1 cells orchestrate responses to pathogens that have overcome epithelial barriers and attack internal tissues. Conversely, Th2 cells arm epithelial and mucosal sites to make life difficult for pathogens attempting to prosper there. Since naive CD4+ T cells can adopt either of these two fates, a central conundrum remains: how do MHCpeptide complexes convey sufficient information to newly activated T cells to enable them to acquire the appropriate effector function in the periphery? Distinct dendritic cell populations may play a role in relaying information that allows naive T cells to anticipate what is to come 1., 2.. Alternatively, the inflammatory milieu in the peripheral tissue may set the final effector repertoire by a combinatorial mix of signals assimilated through cytokine, costimulatory and chemokine receptors 3., 4., 5..

Current paradigms envision a major role for the cytokines IL-4 and IL-12 in providing permissive signals that favor polarization by directly activating the cytokines IL-4 and IFN-γ, respectively, while at the same time reinforcing expression of the canonical master regulators GATA-3 and T-bet (Fig. 1). Here, we update information published during the past year suggesting that effector T cells may acquire their restricted cytokine repertoire by selective silencing of activated genes rather than by activation of distinct expression patterns. The factors that turn cytokine gene expression on and off at different stages of differentiation and that open up or close down gene accessibilty will be detailed.

Section snippets

Opening up

Current evidence for Th differentiation supports a model whereby progressive chromatin remodeling and DNA demethylation render otherwise quiescent cytokine loci accessible to activation-induced transcription factors that ultimately define lineage fate.

Kinetic studies reveal specific DNase I hypersensitivity sites within 2 days and gene demethylation after 47 days at the respective cytokine loci following polarization of naive CD4+ T cells 6., 7.. Using a minilocus construct linking Th2-induced

Closing down

The presence of GATA-3 mRNA in naive T cells [27] and induction of T-bet mRNA after cell activation, even in the absence of Stat1-mediated signals [22••], are consistent with the early transcription of IFNγ and IL-4 after stimulation [21••]. Cells activated in the absence of either IL-12 or IL-4 express both transcriptional activators [28•]. Although GATA-3 and T-bet were identified on the basis of their capacity to activate canonical cytokines in developing Th subsets, in each case these

Conclusions

The shift from a paradigm of constrained expression to generalized activation and constrained silencing invites speculation regarding how such mechanisms are established (Fig. 2). The observation that cells that have undergone few cell divisions retain pluripotent Th fates 21••., 28•. suggests that cells initially activated within lymph nodes may remain uncommitted. Indeed, cells recovered after cytokine-neutral rounds of division can be re-expanded to become either canonical Th1 or Th2

Update

Two recent publications report the phenotype of T-bet-knockout mice. As predicted by the arguments presented here, T-bet-deficient CD4+ T cells spontaneously develop into Th2 effectors in response to environmental respiratory antigens, resulting in a natural model for allergic airways diseases like asthma [60••]. Unexpectedly, T-bet, although necessary for IFNγ expression by CD4+ T cells and NK cells, was not required for IFNγ expression by CD8+ T cells [61]. This observation cautions that

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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