Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY.
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY.
J Allergy Clin Immunol. 2018 Jun;141(6):2107-2120. doi: 10.1016/j.jaci.2017.11.060. Epub 2018 Jan 31.
The contribution of phenotypic variation of peanut-specific T cells to clinical allergy or tolerance to peanut is not well understood.
Our objective was to comprehensively phenotype peanut-specific T cells in the peripheral blood of subjects with and without peanut allergy (PA).
We obtained samples from patients with PA, including a cohort undergoing baseline peanut challenges for an immunotherapy trial (Consortium of Food Allergy Research [CoFAR] 6). Subjects were confirmed as having PA, or if they passed a 1-g peanut challenge, they were termed high-threshold subjects. Healthy control (HC) subjects were also recruited. Peanut-responsive T cells were identified based on CD154 expression after 6 to 18 hours of stimulation with peanut extract. Cells were analyzed by using flow cytometry and single-cell RNA sequencing.
Patients with PA had tissue- and follicle-homing peanut-responsive CD4 T cells with a heterogeneous pattern of T2 differentiation, whereas control subjects had undetectable T-cell responses to peanut. The PA group had a delayed and IL-2-dependent upregulation of CD154 on cells expressing regulatory T (Treg) cell markers, which was absent in HC or high-threshold subjects. Depletion of Treg cells enhanced cytokine production in HC subjects and patients with PA in vitro, but cytokines associated with highly differentiated T2 cells were more resistant to Treg cell suppression in patients with PA. Analysis of gene expression by means of single-cell RNA sequencing identified T cells with highly correlated expression of IL4, IL5, IL9, IL13, and the IL-25 receptor IL17RB.
These results demonstrate the presence of highly differentiated T2 cells producing T2-associated cytokines with functions beyond IgE class-switching in patients with PA. A multifunctional T2 response was more evident than a Treg cell deficit among peanut-responsive T cells.
花生特异性 T 细胞表型变异对花生过敏或耐受的临床意义尚不清楚。
本研究旨在全面表型分析过敏或耐受人群外周血中的花生特异性 T 细胞。
研究纳入过敏患者，包括正在接受免疫治疗试验基线花生挑战的队列（食物过敏研究联盟[CoFAR] 6）。过敏患者经临床诊断确诊，或在通过 1g 花生挑战后被称为高阈值患者。同时纳入健康对照（HC）。通过在花生提取物刺激 6-18 小时后检测 CD154 的表达来鉴定花生反应性 T 细胞。通过流式细胞术和单细胞 RNA 测序分析细胞。
过敏患者具有组织和滤泡归巢的花生反应性 CD4 T 细胞，具有异质性的 T2 分化模式，而对照受试者对花生无 T 细胞反应。PA 组的 CD154 表达延迟且依赖于 IL-2，而 HC 或高阈值组则不存在这种情况。Treg 细胞耗竭增强了 HC 受试者和过敏患者体外的细胞因子产生，但与高度分化的 T2 细胞相关的细胞因子对 Treg 细胞的抑制作用更具抵抗力。通过单细胞 RNA 测序进行的基因表达分析鉴定了具有 IL4、IL5、IL9、IL13 和 IL-25 受体 IL17RB 高度相关表达的 T 细胞。
这些结果表明，在过敏患者中存在产生 T2 相关细胞因子的高度分化的 T2 细胞，其功能超出 IgE 类别转换。在花生反应性 T 细胞中，多功能 T2 反应比 Treg 细胞缺陷更为明显。
