T helper 2 (Th2) cell differentiation, type 2 innate lymphoid cell (ILC2) development and regulation of interleukin-4 (IL-4) and IL-13 production

Abstract

Interleukin-4 (IL-4), IL-5 and IL-13, the signature cytokines that are produced during type 2 immune responses, are critical for protective immunity against infections of extracellular parasites and are responsible for asthma and many other allergic inflammatory diseases. Although many immune cell types within the myeloid lineage compartment including basophils, eosinophils and mast cells are capable of producing at least one of these cytokines, the production of these "type 2 immune response-related" cytokines by lymphoid lineages, CD4 T helper 2 (Th2) cells and type 2 innate lymphoid cells (ILC2s) in particular, are the central events during type 2 immune responses. In this review, I will focus on the signaling pathways and key molecules that determine the differentiation of naïve CD4 T cells into Th2 cells, and how the expression of Th2 cytokines, especially IL-4 and IL-13, is regulated in Th2 cells. The similarities and differences in the differentiation of Th2 cells, IL-4-producing T follicular helper (Tfh) cells and ILC2s as well as their relationships will also be discussed.

Keywords: GATA3; Interleukin-13; Interleukin-4; Type 2 T helper cells (Th2); Type 2 innate lymphoid cells (ILC2).

Figure 1. Transcriptional network and positive feedback regulation during Th2 cell differentiation

TCR activation and cytokine-mediated signaling are critical during Th2 cell differentiation. TCR stimulation activates NFAT, NFκb and AP-1 family members, resulting in up-regulation of IRF4 expression, which has a general function in T cell activation. Low dose of antigen stimulation accompanied by the up-regulation of Th2 master regulator GATA3 favors Th2 cell differentiation. IL-4-mediated Stat6 activation and other signaling pathways such as Notch-mediated signaling are also capable of inducing GATA3 expression. GATA3 directly mediates epigenetic modifications at the Th2 cytokine locus and cytokine transcription. GATA3 also indirectly regulates Th2 cytokine expression by inducing other transcription factor some of which may further up-regulate GATA3 expression. GATA3 also regulates its own expression. IL-2-mediated Stat5 activation is another key event for Th2 cytokine production. Activated T cells are able to produce both IL-2 and IL-4, and to up-regulate IL-2 and IL-4 receptors, forming a powerful positive feedback loop.

Figure 2. Similarity between Th2 cells and ILC2s

Both Th2 cells and ILC2s are capable of producing a set of cytokines such as IL-5, IL-13 and Amphiregulin (Areg), although ILC2s produce less IL-4 and no parathyroid hormone (Pth). GATA3 is critical for the development, maintenance and functions of both Th2 cells and ILC2s. While ILC2s lack T cell receptor (TCR), they express cytokine receptors found on Th2 cells including IL-33 receptor (T1/ST2), IL-2 receptor and IL-7 receptor. Both Th2 cells and ILC2s produce IL-5 and IL-13 when stimulated through IL-33 and a Stat5 activator such as IL-2 and IL-7. Th2 cells and ILC2s also share expression of specific chemokine receptors including CRTh2, CCR8, CCR1 etc. Similar gene expression between Th2 cells and ILC2s and their dependence on GATA3 is consistent with their similar functions during type 2 immune responses.