Basophils Are the Major Producers of IL-4 during Primary Helminth Infection

Abstract

IL-4 production by leukocytes is a key regulatory event that occurs early in the type-2 immune response, which induces allergic reactions and mediates expulsion of parasites. CD4+ T-cells and basophils are thought to be the key cell types that produce IL-4 during a type-2 response. Here, we assessed the relative contribution of both CD4+ T-cell- and basophil-IL-4 production during primary and secondary responses to Nippostrongylus brasiliensis using a murine IL-4-eGFP reporter system. During infection, IL-4 producing basophils were detected systemically and tissue recruitment occurred independent of IL-4/STAT6 signaling. We observed that basophil recruitment to a tissue environment was required for their full activation. Basophil induction in response to secondary infection exhibited accelerated kinetics in comparison to primary infection. However, total basophil numbers were not enhanced, as predicted by previous models of protective immunity. Overall, the induction and migration of IL-4 producing basophils into peripheral tissues was found to be a prominent characteristic of the primary, but not memory responses to N. brasiliensis infection where CD4+ T-cells were identified as the major source of IL-4. While basophils were the major initial producers of IL-4 we determined that normal TH2 differentiation occurs independently of basophils and depletion of basophils led to an enhancement of inflammatory cell recruitment to the site of infection.

The Receptor For Advanced Glycation End-Products Is A Central Mediator Of Asthma Pathogenesis

“…Thus, IL-4 induction in the absence of the other two canonical Th2 cytokines could be reflective of either uncoupling in the cytokine response at the T-cell level or the recruitment of other cell types that may produce IL-4, such as macrophages 40 or basophils. 41 The fact that immunoglobulin production in response to antigens occurs in the absence of RAGE, despite the lack of other features associated with AAD, is consistent with prior studies suggesting that B-cell deficiency (and hence immunoglobulin production) does not affect the physiologic and pathologic changes seen in response to antigen sensitization and challenge in an ovalbumin mouse model of asthma/ AAD. 42 Furthermore, the fact that in the presence of high levels of IgE the RAGE KO mice do not develop airway hypersensitivity, eosinophilia, or remodeling would seem to indicate that IgE alone is not playing a central mechanistic role in this model of asthma, although it must be noted that changes in airway physiology were assayed with graded doses of methacholine rather than allergen.…”

Type 2 Innate Immunity in Helminth Infection Is Induced Redundantly and Acts Autonomously following CD11c+Cell Depletion

“…Following N. brasiliensis infection, basophilia is known to develop rapidly from day 3 following infection (33,38,54,60,65). Rather than use genetic models of basophil deficiency (39,60), which may affect the baseline levels of innate populations, we chose to treat mice with the monoclonal antibody MAR-1, as described by other authors (10,15,24,45,57,63), which eliminated Ͼ90% of circulating …”

“…Basophils have also been identified as participants in Th2 immunity, in general as amplifiers through production of IL-4 (22,33,65), and are indeed the main source of IL-4 in primary infection with the gastrointestinal nematode Nippostrongylus brasiliensis (65). In some models, including Trichuris muris infection, basophils have also been reported to be essential for initiation of Th2 responses (44,58).…”

“…In other systems, however, basophils appear to be less critical for inducing primary Th2 differentiation. Thus, IL-3 or IL-3 receptor (IL-3R)-deficient mice show intact Th2 responses to N. brasiliensis in the absence of basophil recruitment (24), and antibody-mediated basophil depletion does not diminish Th2 induction in infection (24,45,65). Likewise, in transgenic constructs of basophil-specific lineage ablation, normal Th2 responsiveness to N. brasiliensis is observed (39,60).…”

A Crystallin Fold in the Interleukin-4-inducing Principle of Schistosoma mansoni Eggs (IPSE/α-1) Mediates IgE Binding for Antigen-independent Basophil Activation

“…The absence of IL-4 signaling in Schistosoma mansoni-infected mice, which are unable to produce IL-4 (IL-4 Ϫ/Ϫ mice) or to react to IL-4 (IL-4 receptor ␣-chain Ϫ/Ϫ mice), is associated with massive intestinal inflammation and rapid death (3,4). Recent studies suggest that basophils are involved in anti-helminth immunity (5,6). They have been shown to migrate to parasite-affected tissues, where they become fully activated and represent the major source of IL-4.…”