GATA3 Regulates the Development and Functions of Innate Lymphoid Cell Subsets at Multiple Stages

Abstract

Innate lymphoid cells (ILCs) are regarded as the innate counterpart of effector CD4 T helper (Th) cells. Just as Th cells, ILCs are classified into distinct subsets based on their functions that are delivered mainly through effector cytokine production. Both ILCs and Th cells play critical roles in various protective immune responses and inflammatory diseases. Similar to Th cell differentiation, the development of ILC subsets depends on several master transcription factors, among which GATA3 is critical for the development and maintenance of type 2 ILCs (ILC2s). However, GATA3 is expressed by all ILC subsets and ILC progenitors, albeit at different levels. In a striking parallel with GATA3 function in T cell development and differentiation, GATA3 also has multiple functions in different ILCs at various stages. In this review, I will discuss how quantitative and dynamic expression of GATA3 regulates the development and functions of ILC subsets.

Keywords: GATA3 transcription factor; cytokines; development; innate lymphoid cells; transcriptional activation.

Figure 1

Symmetry between the development of adaptive and innate lymphocytes. There are following three major T helper (Th) subsets: Th1, Th2, and Th17 cells. Transcription factors T-bet, GATA3, and RORγt are the master regulators for the differentiation of Th1, Th2, and Th17 cells, respectively, from naïve CD4 T cells. Th2 cells express high levels of GATA3 that is critical for the development and functional maintenance of Th2 cells. The importance of low GATA3 expression in Th1 and Th17 cells is not clear. During T cell development, GATA3 is critical for the development of CD4 but not CD8 T cells in the thymus. Similarly, GATA3 is indispensable for the development of all IL-7Rα-expressing helper-like innate lymphoid cells (ILCs) but not natural killer (NK) cells. While GATA3 is critical for the functional maintenance of ILC2s, it is also required for the homeostasis, function, and further maturation of other ILCs, including ILC1s and ILC3s. Although GATA3 is not necessary for the development of NK and CD8 T cells, GATA3 expression at low levels contributes to the homeostasis and maturation of these cells. EILP, early ILC progenitor that expresses TCF7; ChILP, common helper-like ILC progenitor that expresses Id2.

Figure 2

GATA3 regulates innate lymphoid cell (ILC) development and functions at multiple stages. GATA3 is expressed by all ILCs including lymphoid tissue inducer (LTi) cells and natural killer (NK) cells, albeit at different levels. GATA3 is required for the development of IL-7Rα-expressing ILCs but not NK cells as shown in Figure 1. At a possible developmental branch point for the bifurcation of PD-1⁺ PLZF-expressing ILC progenitors (ILCPs) and CCR6⁺ LTi progenitors, GATA3 is highly expressed in and absolutely required for the generation of “non-LTi” PLZF-expressing ILCPs. High level of GATA3 expression may suppress LTi developmental program. Nevertheless, GATA3 expression at low levels during the early stage of LTi cell development regulates LTi function. In mature ILCs, GATA3 is required for the functions and maintenance of ILC2s. GATA3 is also important for the homeostasis of ILC1s. Furthermore, the development of NKp46⁺ ILC3s that co-express T-bet and RORγt depends on low levels of GATA3 expression. Finally, GATA3 promotes IL-22 production in RORγt-expressing ILCs and regulates IL-7Rα expression in all ILC subsets. EILP, early ILC progenitor that expresses TCF7, NFIL3, and Tox; ChILP, common helper-like ILC progenitor that expresses Id2; ILCP, common ILC progenitor that expresses PLZF and GATA3.