Alternatively activated dendritic cells regulate CD4⁺T-cell polarization in vitro and in vivo

Abstract

Interleukin-4 is a cytokine widely known for its role in CD4 + T cell polarization and its ability to alternatively activate macrophage populations. In contrast, the impact of IL-4 on the activation and function of dendritic cells (DCs) is poorly understood. We report here that DCs respond to IL-4 both in vitro and in vivo by expression of multiple alternative activation markers with a different expression pattern to that of macrophages. We further demonstrate a central role for DC IL-4Rα expression in the optimal induction of IFNγ responses in vivo in both Th1 and Th2 settings, through a feedback loop in which IL-4 promotes DC secretion of IL-12. Finally, we reveal a central role for RELMα during T-cell priming, establishing that its expression by DCs is critical for optimal IL-10 and IL-13 promotion in vitro and in vivo. Together, these data highlight the significant impact that IL-4 and RELMα can have on DC activation and function in the context of either bacterial or helminth pathogens.antigen presenting cells | T lymphocytes | innate immunity | adaptive immunity

CD300f associates with IL-4 receptor α and amplifies IL-4–induced immune cell responses

“…+ T cells into Th2 cells (1). Furthermore, IL-4 and IL-13 can activate multiple cells of the myeloid lineage, including macrophages, dendritic cells, and eosinophils (2,3). For example, IL-4/IL-13-activated myeloid cells display an alternatively activated phenotype, which is associated with the induction of a distinct genetic signature, including the expression of specific mediators and enzymes (4).…”

Comparison of RELMα and RELMβ Single- and Double-Gene-Deficient Mice Reveals that RELMα Expression Dictates Inflammation and Worm Expulsion in Hookworm Infection

“…Additionally, in ovalbumin-induced allergic airway inflammation, RELM␣ overexpression led to reduced levels of Th2 cytokines in the lung (14). RELM␣ is also expressed by dendritic cells in response to interleukin-4 (IL-4), where it is important for the early priming of CD4 ϩ Th2 cells (15). In contrast, RELM␤ is expressed by intestinal epithelial cells following helminth infection.…”

Schistosoma mansoni Hemozoin Modulates Alternative Activation of Macrophages via Specific Suppression of Retnla Expression and Secretion

“…Similarly, the direct binding of Retnla to T cells and macrophages was shown to specifically inhibit these cells' production of IL-4, IL-13, and IL-5, while Retnla Ϫ/Ϫ aaM⌽s promoted exaggerated antigen-specific Th2 cell differentiation (22). Furthermore, Retnla derived from alternatively activated dendritic cells has been shown to promote IL-10 production by T cells (21). Thus, Retnla represents one of the many host mechanisms employed to limit and modulate the pathological Th2 inflammatory response to parasite eggs.…”

“…Thus, we propose that hemozoin is both temporally and spatially well placed to modulate important immunopathogenic events in the liver during chronic schistosomiasis. We further demonstrate that purified S. mansoni hemozoin modulates the alternative activation of macrophages in vitro by specifically downregulating the expression and secretion of Retnla (also known as Fizz1 [19] or Relm␣ [20]), a factor known to be involved in the regulation of Th2 responses during experimental schistosomiasis (21)(22)(23). As such, hemozoin not only represents an important detoxification mechanism in this parasite but also may be essential in modulating the host-protective granulomatous response.…”