Mechanisms of allergy and clinical immunology
CD34+ hemopoietic progenitor cells are potent effectors of allergic inflammation

https://doi.org/10.1016/j.jaci.2008.10.022Get rights and content

Background

In steady state, hemopoietic progenitors constantly egress from the bone marrow (BM) into the blood and circulate through the peripheral tissues. In allergic diseases, the BM releases increased numbers of CD34+ progenitor cells that migrate to the site of allergic inflammation, where they differentiate into tissue-dwelling and classic effector cells of allergy, such as mast cells, eosinophils, and basophils.

Objective

To examine whether peripheral blood CD34+ cells in addition to being progenitors may also directly function as inflammatory effector cells.

Methods

Highly purified neonatal or adult blood CD34+ cells were examined for the expression of thymic stromal lymphopoietin (TSLP) and IL-33 receptors and for their response to these cytokines as well as to supernatants of primary small airway epithelial cells and nasal explants from rhinosinusitis and control subjects. Sputum of patients with asthma was examined before and after allergen inhalation for the presence of IL-5 and IL-13–containing CD34+ cells.

Results

Circulating CD34+ cells expressed receptors for TSLP and IL-33 and responded to these cytokines by rapidly releasing high levels of proinflammatory TH2-like cytokines and chemokines. These cells were activated in a TSLP-dependent manner by the supernatant fluids from activated primary human small airway epithelial cells and from nasal explants of patients with chronic rhinosinusitis. Moreover, activated CD34+ cells containing IL-5 and IL-13 could be detected in the sputum of individuals with allergic asthma, with numbers increasing in response to specific allergen inhalation challenge.

Conclusion

Blood CD34+ cells, in addition to being progenitors, may act as proinflammatory effector cells by themselves and directly contribute to the allergic inflammation.

Section snippets

CD34+ cell cultures

CD34+ progenitor cells were positively selected from umbilical cord blood by double passage through columns (Miltenyi Biotech, Auburn, Calif) leading to cellular preparations containing more than 98% CD34+ cells and negative for CD3, CD10, CD14, CD19, CD20, CD40, CD56, CD83, CDw125 (IL-5 receptor), and FcɛR1. CD34+ cells were cultured at 1 × 104 cells/mL in 0.2 mL in 96-well flat-bottom plates overnight in the presence of exogenous cytokines and neutralizing antibodies (+/−), as indicated.

Human CD34+ progenitor cells express functional receptors for TSLP and IL-33

Given the important role ascribed to TSLP and IL-33 in allergic diseases, we first sought to determine whether CD34+ cells expressed functional receptors for these cytokines. As shown in Fig 1, A, highly purified freshly isolated CD34+ cells expressed receptors for TSLP (TSLP-R and IL-7 Rα)21 and IL-33 (ST2 and IL-1 receptor accessory protein [AcP])22 at mRNA and protein levels. Overnight stimulation of freshly isolated CD34+ cells with TSLP in combination with IL-33 induced cytokine expression

Discussion

In steady-state conditions, hemopoietic progenitors constantly egress from BM into blood and circulate through the peripheral tissues, where they may differentiate into tissue-resident cells. In allergic diseases, the BM releases increased numbers of CD34+ progenitors that migrate to the sites of allergic inflammation, where they differentiate into MCs, eosinophils, and basophils, the typical effector cells of allergic responses. The current data indicate that in addition to being hemopoietic

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    Supported by a grant from Amgen Inc. Z.A. is a recipient of the Parker B. Francis fellowship.

    Disclosure of potential conflict of interest: M. R. Comeau is employed by Amgen, Inc. L. M. Endam and M. Derosiers have received research support from the Foundation Antoine Turmel. G. M. Gauvreau has served as a consultant for MedImmune, Icagen, and Altair and has received research support as an investigator from Schering-Plough and MedImmune. The rest of the authors have declared that they have no conflict of interest.

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