Basophils Initiate IL-4 Production during a Memory T-dependent Response

Abstract

Experiments were performed to characterize and identify the cellular sources of the secondary interleukin (IL)-4 response to a T cell–dependent antigen. Mice were primed by immunization with goat anti–mouse immunoglobulin (Ig)D antibody (GaMD), which stimulates naive CD4+ T cells to secrete IL-4 in 3–4 d. When challenged with goat serum 14 d after immunization, GaMD-primed mice generated an IL-4 response that exceeded the primary response by ∼100-fold, started in <2 h, and lasted for 4 d. Studies with 4get mice, in which cells with an accessible Il4 gene express a green fluorescent protein (GFP), revealed CD4+ memory T cells, natural killer T cells, basophils, mast cells, and eosinophils as possible rapid producers of IL-4. GFP+CD4+ T cells and basophils expanded more in the spleen than the other cell types during the primary response to GaMD. Quantitation of in vivo IL-4 production by the in vivo cytokine capture assay after individual cell types were selectively stimulated or deleted demonstrated that basophils and memory CD4+ T cells account for most of the secondary IL-4 response, with basophils initiating that response through IgE/FcɛRI-mediated signaling but secreting IL-4 for <4 h and memory T cells secreting IL-4 within 4 h and continuing to secrete this cytokine for 4 d.

A central regulatory role for eosinophils and the eotaxin/CCR3 axis in chronic experimental allergic airway inflammation

“…Our data showing that murine CCR3 is predominantly expressed by eosinophils are consistent with previous studies (19,20). These observations suggest that leukocyte recruitment in chronic allergic inflammation is orchestrated, at least in part, via CCR3 signaling in eosinophils, although we cannot exclude signal transduction events in other cells such as basophils and epithelial cells, because they have been shown to express low levels of CCR3 at least in the human system (21,22). Interestingly, only eosinophil trafficking is impaired in the eotaxin-1͞2-deficient mice, suggesting that other CCR3 ligands provide sufficient stimulation to induce the infiltration by other cell types.…”

Identification of markers that distinguish IgE- from IgG-mediated anaphylaxis

“…Although we cannot prove that changes similar to those observed in mice can distinguish human IgE-mediated anaphylaxis from putative IgG-mediated anaphylaxis, previous observations and our preliminary studies are consistent with this possibility: (i) human basophils, like mouse basophils, are induced to secrete IL-4 by FcεRI cross-linking (32) This view is reinforced by the fact that the differences between markers for IgE-and IgG-mediated anaphylaxis make sense: although basophils express both FcεRI and FcγRIII and can be activated through both Rs, only activation through FcεRI induces a strong IL-4 response (25,33), which, in turn, induces increases in both soluble and T-cell membrane IL-4Rα expression. Similarly, although mast cells can be induced under special conditions to release granules that contain MMCP1 in response to FcγRIII cross-linking (34), FcεRI cross-linking is normally a much more potent trigger for mast cell degranulation.…”

Differences in Expression, Affinity, and Function of Soluble (s)IL-4Rα and sIL-13Rα2 Suggest Opposite Effects on Allergic Responses

“…The ease with which these complexes dissociate suggests that sIL-4R␣ functions primarily as a carrier protein for IL-4 that increases its in vivo half-life sufficiently to increase the biological effect of secreted IL-4 and allow it to act at sites distant from its site of secretion. This function may become most apparent when large amounts of IL-4 are secreted over a short period of time, as happens physiologically when Ag activates basophils by crosslinking basophil-associated IgE (19). The relatively low in vivo affinity of sIL-4R␣ for IL-4 also makes it unlikely that this molecule will inhibit IL-4 binding to cell membrane type 1 or type 2 IL-4R heterodimers, which have similar, very high affinities for IL-4.…”

“…To evaluate this possibility, experiments were performed that determined sIL-4R␣ saturation with IL-4 during a rapid in vivo IL-4 response. Priming of mice with an anti-IgD mAb followed by challenge with an anti-IgE mAb, which induces massive basophil IL-4 and IL-13 secretion over a 4-h period (19), had little effect on serum levels of sIL-4R␣ or sIL-13R␣2 but increased sIL-4R␣ saturation with IL-4 from 0 to ϳ8% and sIL-13R␣2 saturation with IL-13 from ϳ20 to ϳ60% (Fig. 4).…”