Center for Immunology & Inflammatory Diseases, Massachusetts General Hospital, Boston, Mass; Harvard Medical School, Boston, Mass.
Center for Immunology & Inflammatory Diseases, Massachusetts General Hospital, Boston, Mass.
J Allergy Clin Immunol. 2021 Jul;148(1):182-194.e4. doi: 10.1016/j.jaci.2020.11.047. Epub 2020 Dec 27.
Peanut is a potent inducer of proallergenic T2 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.
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.
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 cells.
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 cells cocultured with PN-stimulated mDCs showed an RA-dependent 4-fold increase in production of IL-5 and expression of integrin αβ.
PN induces RALDH2 in human APCs by signaling through the TLR1/TLR2 heterodimer. This leads to production of RA, which acts on T cells to induce IL-5 and gut-homing integrin. RALDH2 induction by PN in APCs and RA-promoted T2 differentiation could be an important factor determining allergic responses to peanut.
花生是一种能在易感个体中诱导潜在过敏原 T2 反应的物质。抗原呈递细胞（APCs），包括树突状细胞和单核细胞，指导幼稚 T 细胞分化为各种效应细胞，决定着免疫反应，如过敏和耐受。
我们试图检测花生蛋白（PN）诱导的人髓样树突状细胞（mDCs）和单核细胞中基因表达的变化，鉴定介导这些变化的信号受体，并评估 mDCs 中 PN 诱导的基因如何影响其促进 T 细胞分化的能力。
从血库供体和花生过敏患者中分离 mDCs、单核细胞和幼稚 CD4 T 细胞。用 PN 和其他刺激物孵育 APCs，并用微阵列和 RT-qPCR 测量基因表达。为了评估 T 细胞分化，将 mDCs 与幼稚 T 细胞共培养。
PN 在 mDCs 中诱导了一个独特的基因表达谱，包括编码视黄醛脱氢酶 2（RALDH2）的基因，RALDH2 是产生视黄酸（RA）途径中的限速酶。PN 刺激 mDCs 也诱导 RALDH2 的酶活性增加 7 倍。针对 TLR1/TLR2 的阻断抗体，以及针对 TLR1/TLR2 的小干扰 RNA，使 PN 刺激的 APCs 中 RALDH2 的表达减少了 70%。与 PN 刺激的 mDCs 共培养的幼稚 T 细胞表现出依赖 RA 的 4 倍增加的 IL-5 产生和整合素 αβ 的表达。
PN 通过 TLR1/TLR2 异二聚体信号诱导人 APCs 中的 RALDH2。这导致 RA 的产生，RA 作用于 T 细胞诱导 IL-5 和肠道归巢整合素。APCs 中 PN 诱导的 RALDH2 和 RA 促进的 T2 分化可能是决定对花生过敏反应的一个重要因素。
