The differential expression of IL-4 and IL-13 and its impact on type-2 immunity

Abstract

Allergic disease represents a significant global health burden, and disease incidence continues to rise in urban areas of the world. As such, a better understanding of the basic immune mechanisms underlying disease pathology are key to developing therapeutic interventions to both prevent disease onset as well as to ameliorate disease morbidity in those individuals already suffering from a disorder linked to type-2 inflammation. Two factors central to type-2 immunity are interleukin (IL)-4 and IL-13, which have been linked to virtually all major hallmarks associated with type-2 inflammation. Therefore, IL-4 and IL-13 and their regulatory pathways represent ideal targets to suppress disease. Despite sharing many common regulatory pathways and receptors, these cytokines perform very distinct functions during a type-2 immune response. This review summarizes the literature surrounding the function and expression of IL-4 and IL-13 in CD4+ T cells and innate immune cells. It highlights recent findings in vivo regarding the differential expression and non-canonical regulation of IL-4 and IL-13 in various immune cells, which likely play important and underappreciated roles in type-2 immunity.

Keywords: Follicular T-helper cell; Interleukin-13; Interleukin-4; Th2 cell; Type-2 immunity.

Figure 1. Classical and non-classical regulation of type-2 cytokine expression

Th2 cells classically produce IL-4 and IL-13 using the canonical pathway where IL-4 signals through the IL-4 receptor to phosphorylate of STAT6 and increase GATA-3 expression. STAT6 and GATA-3 then promote the expression of IL-4 and IL-13. Tfh cells express IL-4 but not IL-13, and they regulate IL-4 expression in a non-classical manner. Tfh cells do not utlize canonical STAT6 or GATA-3 to induce IL-4 expression. The non-canonical pathways used by Tfh cells to express IL-4 are not clearly defined, but many candidates exist. Th2 cells also can express type-2 cytokines in a STAT6/GATA-3 independent, non-canonical fashion. Green arrows represent regulators that are positively influence cytokine expression. Blue arrows represent molecules that likely influence cytokine production. Red hatches represent molecules that inhibit cytokine production. Solid arrows indicate direct regulation of IL-4 and IL-13. Dashed arrows represent indirect regulation.

Figure 2. Divergent expression and functions of IL-4 and IL-13 highlight two distinct arms of type-2 immunity

During allergic immune response a naïve CD4+ T cells in the paracortex of lymph nodes must make several fate choices. One of which is to become a Th2 cell or a Tfh cell. Although it is clear that committed Tfh cells and Th2 cells represent unique cellular subsets and perform distinct function, it still remains unclear whether these Tfh cells and Th2 cells share a common IL-4-competent precursor (pTh), or whether Tfh and Th2 cells arise from distinct progenitors (pTh2 and pTfh). IL-4 competent CD4+ T cells express IL-4 mRNA in the paracortex, but do not generate protein until the reach the B cell follicle as a Tfh cell or site of allergic inflammation as a Th2 cell. Tfh cells in the follicles and germinal centers secrete IL-4 protein and are essential for humoral immunity. Th2 cells at sights of allergic inflammation produce both IL-4 and IL-13, and contribute to the peripheral aspects of allergic immunity. The peripheral allergic hallmarks are largely dependent on IL-13 expression. Innate immune cells also contribute to the peripheral immune response. Like Tfh and Th2 precursors, innate cells constitutively express cytokine mRNA, but exhibit a distinct preference to secrete either IL-4 or IL-13. ((Light green = IL-4 mRNA expression); Dark Green = IL-4 Protein expression; Yellow = IL-13 protein production)).