IL-3 produced by T cells is crucial for basophil extravasation in hapten-induced allergic contact dermatitis

Abstract

Basophils have been recognized as a characterized cellular player for Th2 immune responses implicated in allergic diseases, but the mechanisms responsible for basophil recruitment to allergic skin remain not well understood. Using a hapten fluorescein isothiocyanate (FITC)-induced allergic contact dermatitis (ACD) mouse model, we show that basophils in FITC-treated IL-3-knockout mice are defective in crossing the vascular endothelium to enter the inflamed skin. By generating mice in which IL-3 is selectively ablated in T cells, we further demonstrate that IL-3 produced by T cells mediates basophil extravasation. Moreover, basophils sorted from FITC-treated IL-3-knockout mice exhibit a decreased expression of integrins Itgam, Itgb2, Itga2b and Itgb7, which are potentially implicated in extravasation process. Interestingly, we observed that these basophils had a reduced expression of retinaldehyde dehydrogenase 1 family member A2 (Aldh1a2), an enzyme responsible for the production of retinoic acid (RA), and administration of all-trans RA restored partially the extravasation of basophils in IL-3-knockout mice. Finally, we validate that IL-3 induces the expression of ALDH1A2 in primary human basophils, and provide further evidence that IL-3 stimulation induces the expression of integrins particularly ITGB7 in an RA-dependent manner. Together, our data propose a model that IL-3 produced by T cells activates ALDH1A2 expression by basophils, leading to the production of RA, which subsequently induces the expression of integrins crucially implicated in basophil extravasation to inflamed ACD skin.

Defining cell type-specific immune responses in a mouse model of allergic contact dermatitis by single-cell transcriptomics

“…In line with our report, a recently published scRNA-seq study of an ovalbumin (OVA)-sensitized murine skin model also unexpectedly found that mast cells/basophils, rather than T cells, are the major source of IL4 and IL13 (Xu et al, 2022). Another recent study showed that basophil-mediated type-2 immune response is mediated by IL3-produced by T cells in the hapten-induced ACD mouse model (Hachem et al, 2023). Future studies investigating cellular interactions between basophils and dFBs will advance our understanding of the basophil chemotaxis mechanism and the role of basophils in skin allergic inflammation.…”

Cutaneous basophil infiltration in atopic dermatitis is associated with abundant epidermal infiltration of helper T cells: A preliminary retrospective study

“…Do basophils interact with CD4 + T cells in skin lesions? A recent murine study revealed that T cells are essential for basophil extravasation in allergic skin inflammation via IL‐3 12 . IL‐3 also induces IL‐4 and IL‐13 secretion from basophils and potentiates the release of proinflammatory mediators and cytokines from basophils 13 .…”

IL-3: key orchestrator of inflammation

“…As for eosinophils, IL-3 plays a key role in basophil survival, migration and activation. Indeed, IL-3 protects basophil from apoptosis in vitro in a Pim1-dependent manner ( 57 ), increases basophil number in the blood during parasite infection ( 34 ), and enables basophil extravasation during allergic contact dermatitis ( 58 ). Moreover, IL-3, alone or in a combination with other molecules, such as anti-FcϵRI mAb, complement component 5a, N-Formylmethionine-leucyl-phenylalanine (fMLP), CCL2 or eotaxin, enhances the expression of various immune mediators important for the function of basophils, such as histamine ( 59 ) or granzyme B ( 60 ).…”