Concerted IL-25R and IL-4Rα signaling drive innate type 2 effector immunity for optimal helminth expulsion

Abstract

Interleukin 25 (IL-25) is a major 'alarmin' cytokine, capable of initiating and amplifying the type immune response to helminth parasites. However, its role in the later effector phase of clearing chronic infection remains unclear. The helminth Heligmosomoides polygyrus establishes long-term infections in susceptible C57BL/6 mice, but is slowly expelled in BALB/c mice from day 14 onwards. We noted that IL-25R (Il17rb)-deficient BALB/c mice were unable to expel parasites despite type 2 immune activation comparable to the wild-type. We then established that in C57BL/6 mice, IL-25 adminstered late in infection (days 14–17) drove immunity. Moreover, when IL-25 and IL-4 were delivered to Rag1-deficient mice, the combination resulted in near complete expulsion of the parasite, even following administration of an anti-CD90 antibody to deplete innate lymphoid cells (ILCs). Hence, effective anti-helminth immunity during chronic infection requires an innate effector cell population that is synergistically activated by the combination of IL-4Rα and IL-25R signaling.

Interleukin-25-mediated resistance against intestinal trematodes does not depend on the generation of Th2 responses

“…Despite these studies, recent works have suggested that the regulatory role of IL-25 may be secondary and this cytokine operates autonomously from Th2 response in the generation of resistance against intestinal helminths [8,16]. Smith and co-workers [8] showed that IL-25 plays a more Herein, we have shown that rIL-13R2 chain limits the ability of mice to respond to E. caproni primary infection, even in the presence of rIL-25. Treatment of mice with both rIL-25 and rIL-13R2 abrogated the response to E. caproni infection and no changes in cytokine levels were observed as a consequence of the infection.…”

“…responses and resistance to infection [9,[31][32][33]36]. Despite these studies, recent works have suggested that the regulatory role of IL-25 may be secondary and this cytokine operates autonomously from Th2 response in the generation of resistance against intestinal helminths [8,16]. Smith and co-workers [8] showed that IL-25 plays a more Herein, we have shown that rIL-13R2 chain limits the ability of mice to respond to E. caproni primary infection, even in the presence of rIL-25.…”

“…Resistance to intestinal helminths is based on the generation of Th2 responses in a complex process that involves the interaction between innate and adaptative mechanisms [5][6][7]. Protective Th2 immunity against intestinal helminths is initiated and amplified by the epithelial-derived alarmin cytokines including IL-25, IL-33 and thymic stromal lymphopoietin (TSLP), though the immune mechanisms behind the development of these responses are poorly understood [6,8]. In recent years, IL-25, a member of the IL-17 family of cytokines also called IL-17E, has been considered a key cytokine.…”

“…Th2-polarized cells release an array of cytokines that drive effector mechanisms and expand themselves through positive feedback loops, amplifying the 5 response [6] . Despite these facts, there are several doubts in relation to the role of IL-25 in the generation of protective Th2 responses to intestinal helminth infections [8,[16][17].…”

“…Likewise, its role in the differentiation of Th cells to memory subset cells and their implications in the generation of immunity against intestinal helminths is unknown. Several recent studies have questioned the role of IL-25 on the generation of adaptive type 2 responses or the differentiation of Th2 cells or their development to effector or memory Th2-cell subsets [8,16].…”