T-bet and Gata3 in controlling type 1 and type 2 immunity mediated by innate lymphoid cells

Innate lymphoid cells (ILCs) are an emerging group of innate lymphocytes that share functional and transcriptional attributes with the various T helper cell effector fates (e.g. Th1, Th2, Th17). ILCs are substantially represented in the intestinal mucosa but are rare in secondary lymphoid organs. They play important roles in epithelial homeostasis, tissue repair and in immunity to intestinal infections. They are also involved in immune-mediated pathology. Here, we will review the emerging roles of the transcription factors T-bet and Gata3 in the development, lineage specification and function of distinct ILC lineages. We will also highlight the requirement of these transcriptional programs for the control of infections and the pathogenesis of inflammatory diseases.

Introduction

Recently, new innate lymphocyte subsets have been identified that are substantially represented at mucosal surfaces of the intestine. These various groups of innate lymphocytes display cytokine effector profiles that strikingly resemble those of the various T helper (Th) cell effector fates (i.e. Th1, Th2, Th17). On the basis of their analogy to Th cell subsets, three groups of innate lymphoid cells (ILCs) have been described; ILC1s, ILC2s and ILC3s [1^••]. The decision to group these innate lymphocyte subsets into one ‘family’ of ILCs is justified by the observation that ILCs share a common transcriptional program that translates into common phenotypic characteristics. For example, each ILC subset expresses the transcriptional regulator Id2 [2^••] and all subsets are absent in mice genetically lacking the Id2 gene [2••, 3, 4, 5]. Most of the ILCs express the interleukin-7 receptor α (IL-7Rα) chain and require IL-7R signaling for differentiation and maintenance [4, 5, 6]. The group designation implies that within one group of ILCs there are several phenotypic distinct subsets with very similar functional and transcriptional characteristics [7]. Group 1 ILCs are predicted to produce type 1 cytokines (i.e. IFN-γ) and to be dependent on T-bet for lineage commitment [7]. As it will be discussed later, a series of recent reports has identified T-bet and IFN-γ-expressing ILCs that may represent ILC1 subsets. Natural killer (NK) cells have also been classified as ILC1s, but they differ in various aspects from the other ILC lineages. While Gata3 or RORγt is required for the development of the ILC2 or ILC3 lineage, respectively, T-bet is not needed for the development of most NK cell subsets [8, 9]. In addition, the majority of human and mouse NK cell populations differ from all other ILC lineages in that they are not affected by IL-7R deficiency and do not express the IL-7R [5, 10, 11]. The notable exception is thymus-derived ‘NK cells’ in mice that require IL-7 for differentiation and/or maintenance [12]. Group 2 ILCs produce type 2 cytokines such as IL-5, IL-9 and IL-13 and require the transcription factor Gata3 for lineage specification. Lastly, group 3 ILCs produce IL-17A, IL-17F and IL-22 and are developmentally dependent on the orphan nuclear receptor RORγt for lineage specification. ILC3s are composed of various distinct subsets, particularly subsets expressing immunoreceptors also found on NK cells such as NKG2D and NKp46. It has been reasoned that NKp46⁺ ILC3s and NKp46⁻ ILC3s may constitute separate lineages because they differ in several cell surface markers and in their cytokine profiles; NKp46⁻ ILC3s but not NKp46⁺ ILC3s produce IL-17A and IL-17F [13, 14]. On the other hand, it was demonstrated that subsets of NKp46⁻ ILC3s can differentiate into NKp46⁺ ILC3s [11, 14].

The interest in the obvious, analogous worlds of Th cell and ILC fates has led to certain important differences being overlooked. The induction of Th cell effector fates requires antigen-specific stimulation and expansion of Th cell clones in a specific cytokine context. In contrast, ILCs upregulate lineage-determining transcription factors as part of their developmental program. Furthermore, the cytokine cues required for Th2 or Th17 commitment are not involved in the specification of the ILC2 and ILC3 lineages because mice lacking the Stat6 or Stat3 signaling required for Th2 or Th17 commitment [15, 16], respectively, have a normal ILC2 and ILC3 compartment [17]. The striking conservation of transcriptional circuitry among innate and adaptive lymphocytes has generated a flurry of reviews that comprehensively cover many aspects of ILC biology [18, 19, 20, 21]. We will focus here on two emerging themes; the role of the transcription factors T-bet and Gata3 in the development and function of ILCs.