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Review
. 2012 Nov;13(11):1037-44.
doi: 10.1038/ni.2431. Epub 2012 Oct 18.

Cytokines of the γ(c) family control CD4+ T cell differentiation and function

Hidehiro Yamane  1 , William E Paul
Affiliations
Review

Cytokines of the γ(c) family control CD4+ T cell differentiation and function

Hidehiro Yamane et al. Nat Immunol. 2012 Nov.

Abstract

Naive CD4(+) T cells undergo massive proliferation and differentiation into at least four distinct helper T cell subsets after recognition of foreign antigen-derived peptides presented by dendritic cells. Each helper T cell subset expresses a distinct set of genes that encode unique transcription factor(s), as well as hallmark cytokines. The cytokine environment created by activated CD4(+) T cells, dendritic cells and/or other cell types during the course of differentiation is a major determinant for the helper T cell fate. This Review focuses on the role of cytokines of the common γ-chain (γ(c)) family in the determination of the effector helper T cell phenotype that naive CD4(+) T cells adopt after being activated and in the function of these helper T cells.

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Figures

Figure 1
Figure 1
A model for early TH2 differentiation. The recognition of an antigen–MHC class II complex (Ag-MHCII) by the TCR on a naive CD4+ T cell leads to the upregulation of GATA-3 expression independently of IL-4 during the early stages of TH2 differentiation. The NF-ºB1-Bcl-3 complex, the Notch-CSL pathway and the Wnt–β-catenin–TCF-1 pathway have been each proposed to have a critical role in TCR-driven GATA-3 expression. GATA-3 binds to several sites on loci encoding TH2 cytokines, ncluding DNase I–hypersensitivity sites II and III (HS II-III) and site V (HS VA) in the Il4 locus. Stimulation via the TCR also induces the production of IL-2 and expression of the IL-2R complex, which results in the activation of STAT5. Activated STAT5 binds to DNase I–hypersensitivity sites II and III, which act together with GATA-3 to induce small amounts of early IL-4 production, and also binds to the IFN-γ-activated GAS3 motif in the Il4ra locus to upregulate IL-4Rα expression.
Figure 2
Figure 2
A model for the regulation of early TH2 differentiation by TCR signal strength. When naive CD4+ T cells receive strong TCR signals (right), prolonged and intense activation of the Erk pathway results in not only the failure to upregulate TCR-driven early expression of GATA-3 but also transient inhibition of IL-2-mediated activation of STAT5, at least during the first 24 hours after stimulation, despite the abundant IL-2 production and IL-2R expression. This defect in both GATA-3 upregulation and STAT5 activation leads to a lack of both early production of IL-4 and subsequent TH2 differentiation. In contrast, when naive CD4+ T cells receive weak TCR signals (left), the degree of activation of the Erk pathway is not strong enough to suppress TCR-driven early expression of GATA-3 or to block STAT5 activation in response to small amounts of IL-2, which allows T cells to generate early production of IL-4 and to undergo subsequent TH2 differentiation.
Figure 3
Figure 3
A model for early determination of iTreg fate versus TH17 fate controlled by TCR signal strength. During early TH17 differentiation phase, naive CD4+ T cells require a combination of the cytokines IL-6 and TGF-β and costimulation (including ICOS), as well as strong TCR signals, to induce the expression of RORγt and TH17 cytokines (right). When naive CD4+ T cells receive weak TCR signals under TH17-polarizing conditions, the differentiation of Foxp3-expressing iTreg cells is favored (left). Although weak TCR signals induce only small amounts of IL-2 production and IL-2R expression, IL-2-mediated STAT5 activation blocks IL-17A production and induces Foxp3 expression, which suppresses the induction of RORγt and thereby favors iTreg differentiation. In contrast, despite abundant IL-2 production and IL-2R expression, transient inhibition of STAT5 activation by strong TCR signals leads to the failure to induce Foxp3 but allows expression of genes encoding RORγt and TH17 cytokines and thereby favors TH17 differentiation. Smad, signal-transducer protein(s) downstream of the receptor for TGF-β (TGF-βR).
Figure 4
Figure 4
A model for early determination of Teff cell fate versus TFH cell fate controlled by TCR signal strength. During the early phase of differentiation into the TFH cell subset, naive CD4+ T cells require the cytokine IL-6 and costimulation (including ICOS), as well as strong TCR signals, to induce the expression of Bcl-6 (right). Although strong TCR signals induce abundant production of IL-2 and expression of the IL-2R complex, transient inhibition of STAT5 activation, presumably through the action of the Erk pathway, leads to the failure to express Blimp-1 and allows Bcl-6 expression induced by IL-6 and stimulation via ICOS and thereby results in differentiation into the TFH cell subset. In contrast, T cells that have received weak TCR signals under TFH cell–polarizing conditions can activate STAT5 in response to small amounts of IL-2, which induces Blimp-1 expression and suppresses Bcl-6 expression and thereby results in ‘preferential’ differentiation into the Teff cell subset (left).
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