Early signaling events that underlie fate decisions of naive CD4(+) T cells toward distinct T-helper cell subsets

Abstract

CD4(+) T-helper (Th) cells are a major cell population that play an important role in governing acquired immune responses to a variety of foreign antigens as well as inducing some types of autoimmune diseases. There are at least four distinct Th cell subsets (Th1, Th2, Th17, and inducible T-regulatory cells), each of which has specialized functions to control immune responses. Each of these cell types emerge from naive CD4(+) T cells after encounter with foreign antigens presented by dendritic cells (DCs). Each Th cell subset expresses a unique set of transcription factors and produces hallmark cytokines. Both T-cell receptor (TCR)-mediated stimulation and the cytokine environment created by activated CD4(+) T cells themselves, by 'partner' DCs, and/or other cell types during the course of differentiation, play an important role in the fate decisions toward distinct Th subsets. Here, we review how TCR-mediated signals in collaboration with the cytokine environment influence the fate decisions of naive CD4(+) T cells toward distinct Th subsets at the early stages of activation. We also discuss the roles of TCR-proximal signaling intermediates and of the Notch pathway in regulating the differentiation to distinct Th phenotypes.

Fig. 1. T-helper cell subsets

Upon TCR recognition of a foreign antigen-derived peptide presented in the context of MHC class II on dendritic cells, naive CD4⁺ T cells undergo massive proliferation and differentiation into distinct T-helper (Th) cell subsets. There are at least four different Th cell subsets (Th1, Th2, Th17 and iTreg) that have distinct functions to regulate immune responses. Each cell subset expresses a unique set of transcription factors as well as hallmark cytokines. The cytokine environment created by activated CD4⁺ T cells themselves, by dendritic cells, and/or other cell types during the course of differentiation plays a critical role in the Th fate decisions. It still remains controversial whether Tfh cells (not depicted in the figure) originate directly from naive CD4⁺ T cells as a distinct subset similar to Th1, Th2, Th17, and iTreg cells or whether Tfh cells emerge from CD4⁺ T cells that have already determined their fates toward either Th1, Th2, or Th17 cell subset.

Fig. 2. Two-step regulation of Th2 differentiation initiated by weak TCR signals

When naive CD4⁺ T cells receive weak TCR signals, these `weakly stimulated' T cells rapidly induce the expression of the Th2 master regulatory transcription factor GATA-3 in an IL-4/STAT6-independent manner and produce IL-2 that in turn activates STAT5. GATA-3 cooperates with STAT5 to induce TCR-dependent, IL-4/STAT6-independent early IL-4 production that occurs 14-24 h after activation (the induction phase). The endogenously produced IL-4 acts on the weakly stimulated T cells through IL-4R to further upregulate GATA-3 expression in a STAT6-dependent manner. The upregulated GATA-3, in collaboration with continued STAT5 activation, amplifies the production of IL-4. This positive feedback loop leads to the completion of differentiation into Th2 cells (the polarization phase).

Fig. 3. Early Th2 fate decision regulated by strength of TCR signals

When naive 5C.C7 CD4⁺ T cells receive strong TCR signals, strong and prolonged ERK activation is induced. This intense ERK activation results in failure to produce early IL-4 by suppressing IL-4-independent TCR-driven early GATA-3 expression and by transiently blocking IL-2R-mediated STAT5 activation (Right). By contrast, when naive 5C.C7 CD4⁺ T cells receive weak TCR signals, the level of ERK activation is not so strong as to suppress early GATA-3 expression or to inhibit the IL-2/STAT5 pathway. GATA-3 and STAT5 subsequently translocate into the nucleus and bind to the DNase hypersensitivity sites II/III and V in the Il4 gene locus, leading to the induction of early IL-4 production, completion of the induction phase and subsequent Th2 polarization process (Left).

Fig. 4. Canonical and noncanonical Notch pathways

In mammals, there are four Notch receptors, Notch 1–4, and five Notch ligands, Jagged (Jag) 1 and 2, and Delta-like (Dll) 1, 3, and 4. When a Notch interacts with a Notch ligand, the γ-secretase complex proteolytically releases the Notch intracellular domain (NICD). NICD translocates into the nucleus, where it displaces a co-repressor complex from CSL and recruits a co-activator complex leading to Notch-dependent gene transcription. CSL-independent functions of NICD have been also reported. The Notch pathway has been proposed to govern differentiation of naive CD4⁺ T cells into each of the Th fates by directly controlling the expression of unique master regulatory transcription factors and hallmark cytokines. An alternative view is that the Notch pathway does not directly instruct Th fate decisions but regulates the basal T-cell activation, T-cell expansion and survival, and cytokine production of differentiated Th cells upon secondary stimulation.