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Peanut protein acts as a Th2 adjuvant by inducing RALDH2 in human antigen-presenting cells

Ruiter, B;Smith, NP;Fleming, E;Patil, SU;Hurlburt, BK;Maleki, SJ;Shreffler, WG;

Peanut is a potent inducer of pro-allergenic Th2 responses in susceptible individuals. Antigen-presenting cells (APC) including dendritic cells and monocytes instruct naïve T cells to differentiate into various effector cells, determining immune responses such as allergy and tolerance. We sought to detect peanut protein (PN)-induced changes in gene expression in human myeloid dendritic cells (mDC) and monocytes, identify signaling receptors that mediate those changes, and assess how PN-induced genes in mDC impact their ability to promote T cell differentiation. mDC, monocytes, and naïve CD4+ T cells were isolated from blood bank donors and peanut-allergic patients. APC were incubated with PN and associated stimulants, then mRNA was isolated for microarray and RT-qPCR. To assess T cell differentiation, mDC were co-cultured with naïve Th cells. PN induced a unique gene expression profile in mDC, including the gene that encodes retinaldehyde dehydrogenase 2 (RALDH2), a rate-limiting enzyme in the retinoic acid (RA)-producing pathway. Stimulation of mDC with PN also induced a 7-fold increase in enzymatic activity of RALDH2. Blocking antibodies against TLR1/TLR2, as well as siRNA targeting TLR1/TLR2, reduced expression of RALDH2 in PN-stimulated APC by 70%. Naïve Th cells co-cultured with PN-stimulated mDC showed an RA-dependent 4-fold increase in production of IL-5 and expression of integrin ?4?7. PN induces RALDH2 in human APC by signaling through the TLR1/TLR2 heterodimer. This leads to production of RA, which acts on Th cells to induce IL-5 and gut-homing integrin. RALDH2 induction by PN in APC and RA-promoted Th2 differentiation could be an important factor determining allergic responses to peanut.