The effects of thymic stromal lymphopoietin and IL‐3 on human eosinophil–basophil lineage commitment: Relevance to atopic sensitization

Abstract

An important immunopathological hallmark of allergic disease is tissue eosinophilic and basophilic inflammation, a phenomenon which originates from hemopoietic progenitors (HP). The fate of HP is determined by local inflammatory cytokines that permit “in situ hemopoiesis,” which leads to the accumulation of eosinophils and basophils (Eo/B). Given that recent evidence supports a critical immunomodulatory role for thymic stromal lymphopoietin (TSLP) in allergic inflammation, as well as TSLP effects on CD34+ progenitor cytokine and chemokine secretion, we investigated the role of TSLP in mediating eosinophilo- and basophilopoiesis, the mechanisms involved, and the association of these processes with atopic sensitisation. In the studies presented herein, we demonstrate a direct role for TSLP in Eo/B differentiation from human peripheral blood CD34+ cells. In the presence of IL-3, TSLP significantly promoted the formation of Eo/B colony forming units (CFU) (including both eosinophils and basophils) from human HP (HHP), which was dependent on TSLP–TSLPR interactions. IL-3/TSLP-stimulated HHP actively secreted an array of cytokines/chemokines, key among which was TNFα, which, together with IL-3, enhanced surface expression of TSLPR. Moreover, pre-stimulation of HHP with IL-3/TNFα further promoted TSLP-dependent Eo/B CFU formation. HHP isolated from atopic individuals were functionally and phenotypically more responsive to TSLP than those from nonatopic individuals. This is the first study to demonstrate enhanced TSLP-mediated hemopoiesis ex vivo in relation to clinical atopic status. The capacity of HHP to participate in TSLP-driven allergic inflammation points to the potential importance of “in situ hemopoiesis” in allergic inflammation initiated at the epithelial surface.

Thymic stromal lymphopoietin activation of basophils in patients with allergic asthma is IL-3 dependent

“…TSLP can promote murine and human bone marrow progenitor cells to differentiate into basophils. 7 Human peripheral CD34 1 cells preincubated with IL-3 and TNF-a have enhanced sensitivity to TSLP-mediated basophil lineage commitment, 8 and mast cell-activated bone marrow mesenchymal stromal cells produce TSLP, which can enhance the differentiation of CD34 1 progenitors into eosinophil/basophil colonies. 9 Furthermore, in the presence or absence of IL-3, TSLP can induce murine basophil receptor changes, including increased CD69, CD62 ligand, CD11b, CD123, IL-33 receptor, and IL-18 receptor expression.…”

A Player and Coordinator: The Versatile Roles of Eosinophils in the Immune System

“…Experimental findings with mouse models also support the crucial roles of eosinophils in TSLP-induced systemic Th2 inflammatory response [98]. Meanwhile it is known that, in the presence of IL-3, TSLP significantly stimulates human hematopoietic progenitors via TSLP-TSLPR interactions to produce eosinophils and basophils colony forming units, promoting the involvement of eosinophils in allergic inflammation [99]. Another interesting recent finding is that TSLP can directly stimulate eosinophils to produce and release eosinophil extracellular traps, one of the efficient machineries for extracellular bacterial killing [100].…”

In situ hematopoiesis: a regulator of TH2 cytokine-mediated immunity and inflammation at mucosal surfaces

“…27 In addition, it has been reported that human CD34 þ progenitor cells express the TSLPR, 34,38 and that TSLP signaling cooperates with other hematopoietic cytokines in the differentiation of human CD34 þ cells. 38 Further, TSLP can directly activate human CD34 þ progenitor cells isolated from peripheral tissues. 34,38 These studies suggest that the TSLP-ISH pathway operates to promote type 2 inflammatory responses in humans.…”

“…For example, HSPCs express the TSLPR and TSLP signaling upregulates IL-3Ra on peripheral blood CD34 þ cells, rendering them more responsive to the effects of IL-3, with concomitant functional Eo/B colony forming unit differentiation. 38 Furthermore, TSLP stimulation of, and signaling in, human CD34 þ HSPCs results in the rapid release of high levels of cytokines and chemokines, further contributing to specific lineage commitment and differentiation. 34,38 Related to this, TSLP induces IL-5 þ / IL-13 þ CD34 þ cells to appear in sputum after airway allergen challenge of atopic asthmatics.…”

“…38 Further, TSLP can directly activate human CD34 þ progenitor cells isolated from peripheral tissues. 34,38 These studies suggest that the TSLP-ISH pathway operates to promote type 2 inflammatory responses in humans. The influence of TSLP on CD34 þ progenitor cells with subsequent development of mucosal inflammation, will be further discussed below.…”