Cytokine-induced cytokine production by conventional and innate lymphoid cells

Abstract

Innate immune and differentiated T cells produce signature cytokines in response to cytokine stimulation. Optimal production requires stimulation by an NF-κB inducer, most commonly an interleukin (IL)-1 family member, and a STAT activator. Usually, there is linkage between the IL-1 family member, the activated STAT and the cytokines produced: IFNγ producers respond to the IL-1 family member, IL-18 and IL-12, a STAT4 activator; IL-13 producers respond to IL-33 (although for ILC2 cells this may be replaced by IL-25) and STAT5 activators; for cells producing IL-17A or IL-22, the combination is IL-1 and a STAT3 inducer. Cytokine-induced cytokine production may have broad significance in orchestrating innate responses to distinct infectious agents and in maintaining inflammatory responses after elimination of the inciting antigen.

Figure 1

Co-stimulating Th2 cells with IL-33 and a STAT5 activator induces IL-13 production. Recently differentiated Th2 cells express high levels of GATA3 and IL-33R. When cells are cultured in medium containing IL-2 or IL-7, which Th2 cells rely on for survival, expression of both GATA3 and IL-33R decline. Upon stimulation with IL-33 and a STAT5 activator, GATA3 transcription is substantially increased. GATA3 and possibly activated STAT5 jointly cause enhanced expression of IL-33R. Upregulated IL-33Rs allow for more efficient IL-33 signal transduction including robust activation of NF-κB, which together with GATA3 and possibly activated STAT5, leads to substantial IL-13 production.

Figure 2

IL-1 family cytokine-induced cytokine production provides a mechanism for a rapid innate response. In a type 2-dominated airway response, respiratory epithelial cells and/or myeloid cells release a variety of cytokines including IL-33, IL-25, and TSLP. These cytokines could be recognized by receptors expressed on innate lymphoid cell (ILC2), natural killer T (NKT) cells, mast cells, basophils, and effector memory Th2 cells to induce IL-13 and IL-5 production, contributing to rapid production of effector cytokines. In parallel, recognition of antigen on dendritic cells (DCs) by antigen-specific naïve and memory CD4 T cells results in cellular activation and proliferation, leading to an adaptive immune response. In intestinal mucosa, where a type 17 response plays a major role, IL-1β and IL-23 produced by mucosal epithelial cells and other cells after microbial invasion could induce innate IL-17 and/or IL-22 production from diverse cell subsets, such as ILC22, ILC17, LTi, NKT, γδ T cells, and effector memory Th17 cells. Such innate IL-17 and/or IL-22 sources are potential important sentinels for immune responses.