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

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.

Figure 1

A model for early T_H2 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 T_H2 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 T_H2 cytokines, ncluding DNase I–hypersensitivity sites II and III (HS II-III) and site V (HS V_A) 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

A model for the regulation of early T_H2 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 T_H2 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 T_H2 differentiation.

Figure 3

A model for early determination of iT_reg fate versus T_H17 fate controlled by TCR signal strength. During early T_H17 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 T_H17 cytokines (right). When naive CD4⁺ T cells receive weak TCR signals under T_H17-polarizing conditions, the differentiation of Foxp3-expressing iT_reg 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 iT_reg 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 T_H17 cytokines and thereby favors T_H17 differentiation. Smad, signal-transducer protein(s) downstream of the receptor for TGF-β (TGF-βR).

Figure 4

A model for early determination of T_eff cell fate versus T_FH cell fate controlled by TCR signal strength. During the early phase of differentiation into the T_FH 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 T_FH cell subset. In contrast, T cells that have received weak TCR signals under T_FH 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 T_eff cell subset (left).