Type 2 cytokine responses: regulating immunity to helminth parasites and allergic inflammation

Abstract

Purpose of review: It is well established that T helper type 2 (T_H2) immune responses are necessary to provide protection against helminth parasites but also to promote the detrimental inflammation associated with allergies and asthma. Given the importance of type 2 immunity and inflammation, many studies have focused on better understanding the factors that regulate T_H2 cell development and activation. As a result, significant progress has been made in understanding the signaling pathways and molecular events necessary to promote T_H2 cell polarization. In addition to the adaptive compartment, emerging studies are better defining the innate immune pathways needed to promote T_H2 cell responses. Given the recent and substantial growth of this field, the purpose of this review is to highlight recent studies defining the innate immune events that promote immunity to helminth parasites and allergic inflammation.

Recent findings: Emerging studies have begun to elucidate the importance of cytokine alarmins such as thymic stromal lymphopoietin (TSLP), IL-25 (IL-17E) and IL-33 in promoting type 2 immunity and inflammation following helminth challenge or exposure to allergens. Specifically, recent reports have begun to define the complex cellular networks these alarmins activate and their contribution to type 2 immunity and inflammation.

Summary: Our increased understanding of the pathways that regulate type 2 cytokine-mediated immunity and inflammation have revealed novel therapeutic targets to treat both helminth infections and allergic disease states.

Keywords: TH2 cells; Type 2 cytokines; allergies and asthma; heminth parasites; innate immunity; mucosal immunology.

Figure 1

Following exposure to helminth parasites or allergens, epithelial cells and some hematopoietic cells produce cytokine alarmins that directly influence ILC2 activation. Activated ILC2s produce robust levels of effector cytokines such as IL-4, IL-5, IL-9, and IL-13 that support the development of immunity and inflammation at barrier surfaces. Further, activated ILC2s also produce Areg that serves to promote the integrity of affected tissues. In addition to cytokine alarmins, recent studies have demonstrated that innate immune cells such as basophils are also capable of directly regulating ILC2 activation. Collectively, these studies demonstrate that distinct mechanisms are capable of influencing ILC2 responses.

Figure 2

A common feature of helminth infections and allergic inflammation is the production of cytokine alarmins by both non hematopoietic and hematopoietic cells. Recent studies have demonstrated that cytokine alarmins are capable of influencing the activation state of several terminally differentiated innate immune cells including mast cells, macrophages, eosinophils, dendritic cells, basophils and ILC2s. In addition to terminally differentiated cells, emerging studies have shown that cytokine alarmins also influence the accumulation and activation of hematopoietic stem/progenitor cells at the barrier surface. Activated HSPCs are capable of undergoing in situ hematopoiesis and differentiating into innate immune cells that further support the development of immunity and inflammation.