Dynamic balance between master transcription factors determines the fates and functions of CD4 T cell and innate lymphoid cell subsets

Abstract

CD4 T cells, including T regulatory cells (Treg cells) and effector T helper cells (Th cells), and recently identified innate lymphoid cells (ILCs) play important roles in host defense and inflammation. Both CD4 T cells and ILCs can be classified into distinct lineages based on their functions and the expression of lineage-specific genes, including those encoding effector cytokines, cell surface markers, and key transcription factors. It was first recognized that each lineage expresses a specific master transcription factor and the expression of these factors is mutually exclusive because of cross-regulation among these factors. However, recent studies indicate that the master regulators are often coexpressed. Furthermore, the expression of master regulators can be dynamic and quantitative. In this review, we will first discuss similarities and differences between the development and functions of CD4 T cell and ILC subsets and then summarize recent literature on quantitative, dynamic, and cell type-specific balance between the master transcription factors in determining heterogeneity and plasticity of these subsets.

Figure 1.

Similarities and differences between the functions and development of T helper (Th) cell and innate lymphoid cell (ILC) subsets. (A) Th cell and ILC subsets express identical sets of effector cytokines and share similar master transcription factors for their development and functions. Th1 cells and ILC1s are important for protective immunity against viruses, intracellular bacteria, and protozoa. Th2 cells and ILC2s are important for clearing helminths. Th17 cells and ILC3s are critical for protective immune responses against fungi and extracellular bacteria infection. Th2 and ILC2s are involved in allergic inflammation, and type 1 and type 3 Th cells and ILCs contribute to autoimmunity. (B) In the thymus, RORγt is essential for CD4⁺CD8⁺ double-positive (DP) cell survival and TCRα rearrangement. CD4⁺CD8⁺ DP thymocytes can develop into naive CD4⁺ T cells, naive CD8⁺ T cells, NKT cells, and tTreg cells through the induction of ThPOK, Eomes, PLZF, and Foxp3, respectively. GATA3 up-regulates ThPOK expression and thus is critical for CD4, but not CD8, T cell development. Upon T cell activation, naive CD4⁺ T cells can further develop into T-bet–expressing Th1, GATA3-expressing Th2, and RORγt-expressing Th17 cells. On the innate side, transcription factor TCF7-expressing NK/ILC progenitor cells can develop into Eomes-expressing conventional NK cells, RORγt-expressing LTi or LTi-like cells, and PLZF⁺GATA3^hiId2^hi ILC progenitors. GATA3 is critical for the generation of PLZF⁺GATA3^hiId2^hi ILC progenitors but not NK cells. PLZF⁺GATA3^hiId2^hi ILC progenitors can further develop into T-bet-expressing ILC1s, GATA3^hi ILC2s and RORγt-expressing ILC3s. RORγt-expressing Th17 cells or ILC3s may further express T-bet to become RORγt/T-bet dual expressing Th1* cells or NKp46⁺ ILC3s. ILCP, ILC progenitor.

Figure 2.

The plasticity of Treg cells. (A) In Treg cells, Foxp3 and RORγt antagonize each other’s function, T-bet and GATA3 cross-regulate each other in Foxp3-expressing Treg cells, and T-bet and GATA3 also repress RORγt in Treg cells in a redundant manner. (B) Depending on the cytokine environment, T-bet or GATA3 can be induced in Foxp3-expressing Treg cells. Dynamic and low expression of T-bet or GATA3 in Treg cells is essential for preventing Treg cells from acquiring the Th1, Th2, or Th17 phenotype. (C) In steady state, T-bet, GATA3, or RORγt can be transiently expressed by Foxp3-expressing Treg cells. During immune responses, Treg cells may have three different fates: (1) Treg cells only expressing Foxp3; (2) specialized Treg cells expressing both Foxp3 and T-bet, GATA3, or RORγt; and (3) T-bet–, GATA3-, or RORγt-expressing Th effectors derived from Treg cells.

Figure 3.

Models for the development of effector cytokine-producing Tfh cells. Bcl6 is the master transcription factor for Tfh cell development. Tfh cells express no or low levels of T-bet, GATA3, or RORγt. IL-21 is the signature effector cytokine of Tfh cells; however, IFN-γ and IL-4 can also be produced by Tfh cells. (A) Model 1. The capacity of Tfh cells to produce IFN-γ or IL-4 is acquired after their development. Low levels of T-bet, GATA3, or RORγt induced by cytokines in Tfh cells are responsible for IFN-γ, IL-4, or IL-17 production, respectively. (B) Model 2. At an early stage of Tfh cell development, transient expression of T-bet, GATA3, or RORγt precommits these Bcl6-expressing Tfh cells to become IFN-γ–, IL-4–, or IL-17–producing Tfh cells in the B cell follicles by leaving “epigenetic memory” marks at the cytokine loci.

Figure 4.

Quantitative, dynamic, and cell type–specific balance between master transcription factors in determining the fates and functions of CD4 T cell and ILC subsets. T-bet, GATA3, and RORγt can be expressed by Th effectors, Treg cells, and ILCs at the single-cell level. The balance between these factors is achieved through quantitative and dynamic expression of each molecule in a cell context–dependent manner. Extracellular stimuli such as cytokines may transiently influence the balance, resulting in cell heterogeneity and plasticity. The alteration of this balance may cause immune-related human diseases. On the other hand, fine-tuning the transcriptional regulatory network may be considered as an effective way to treat certain diseases.TFs, transcription factors.