Peanut protein acts as a TH2 adjuvant by inducing RALDH2 in human antigen-presenting cells

Abstract

Background: Peanut is a potent inducer of proallergenic T_H2 responses in susceptible individuals. Antigen-presenting cells (APCs) including dendritic cells and monocytes instruct naive T cells to differentiate into various effector cells, determining immune responses such as allergy and tolerance.

Objective: We sought to detect peanut protein (PN)-induced changes in gene expression in human myeloid dendritic cells (mDCs) and monocytes, identify signaling receptors that mediate these changes, and assess how PN-induced genes in mDCs impact their ability to promote T-cell differentiation.

Methods: mDCs, monocytes, and naive CD4⁺ T cells were isolated from blood bank donors and peanut-allergic patients. APCs were incubated with PN and other stimulants, and gene expression was measured using microarray and RT quantitative PCR. To assess T-cell differentiation, mDCs were cocultured with naive T_H cells.

Results: PN induced a unique gene expression profile in mDCs, including the gene that encodes retinaldehyde dehydrogenase 2 (RALDH2), a rate-limiting enzyme in the retinoic acid (RA)-producing pathway. Stimulation of mDCs with PN also induced a 7-fold increase in the enzymatic activity of RALDH2. Blocking antibodies against Toll-like receptor (TLR)1/TLR2, as well as small interfering RNA targeting TLR1/TLR2, reduced the expression of RALDH2 in PN-stimulated APCs by 70%. Naive T_H cells cocultured with PN-stimulated mDCs showed an RA-dependent 4-fold increase in production of IL-5 and expression of integrin α₄β₇.

Conclusions: PN induces RALDH2 in human APCs by signaling through the TLR1/TLR2 heterodimer. This leads to production of RA, which acts on T_H cells to induce IL-5 and gut-homing integrin. RALDH2 induction by PN in APCs and RA-promoted T_H2 differentiation could be an important factor determining allergic responses to peanut.

Keywords: IL-5; Peanut allergy; RALDH2; T(H)2; TLR2; dendritic cells; integrin α(4)β(7); monocytes; peanut; retinoic acid.