Shibahara Kyoko, Hoshino Tomohiro, Nakanishi Haruka, Nishitsuji Kosuke, Soga Kohei, Bamba Yoshiyo, Hachimura Satoshi, Nakajima-Adachi Haruyo
Research Center for Food Safety, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
Department of Immunobiology and Biofunctional Research, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
PLoS One. 2025 May 30;20(5):e0324105. doi: 10.1371/journal.pone.0324105. eCollection 2025.
Impaired expansion, stability, and function of regulatory T cells (Tregs) are reported in patients with severe allergy. Transfer of Tregs is a potential means of treating severe food allergy; however, methods to obtain allergen-specific Tregs with stable regulatory activities are needed. To achieve our goal, we examined the characteristics of allergen-specific Tregs by comparing two mouse strains transgenic for the ovalbumin (OVA)-specific T cell receptor gene: Rag23-3 and RagD10 mice (OVA23-3 and DO11.10 crossed with Rag2 knockout mice, respectively). RagD10 is a tolerant model, whereas Rag23-3 shows severe allergy when fed egg white (EW). To examine the differentiation of CD4+ T cells into Foxp3+ Tregs (induced Tregs; iTregs), CD4+ T cells or whole cells from mesenteric lymph nodes or spleens were cultured under Treg-polarization conditions and stimulated with either a combination of anti-CD3 and anti-CD28 antibodies or OVA plus antigen-presenting cells. After stimulation with the antibodies, iTregs were induced at comparable levels from CD4+ T cells from untreated Rag23-3 and RagD10 mice. Transfer of the resultant iTregs from untreated Rag23-3 mice suppressed allergic responses in EW-fed Rag23-3 mice. In contrast, stimulation with OVA plus antigen-presenting cells prevented the differentiation of iTregs from CD4+ T cells from untreated Rag23-3 mice, suggesting that OVA-induced T-cell receptor signaling inhibits effective Treg differentiation. Furthermore, antibody-mediated differentiation afforded significantly more iTregs differentiation of naïve (CD44loCD62Lhi) CD4+ T cells than of effector/effector memory (CD44hiCD62Llo) T cells isolated from the mesenteric lymph nodes of EW-fed Rag-23-3 mice. Excessive production of interleukin-4 and interferon-gamma by CD4+ T cells from EW-fed Rag23-3 mice significantly inhibited Treg induction in RagD10 mice, suggesting the severe allergic cytokine milieu likely prevents their differentiation. However, our study showed that allergen-specific Tregs with regulatory activity can be obtained from naïve CD4+ T cells from the intestinal immune system of mice even with severe allergy.
据报道，严重过敏患者体内调节性T细胞（Tregs）的扩增、稳定性及功能受损。Tregs转移是治疗严重食物过敏的一种潜在方法；然而，需要获得具有稳定调节活性的过敏原特异性Tregs的方法。为实现我们的目标，我们通过比较两种转卵清蛋白（OVA）特异性T细胞受体基因的小鼠品系来研究过敏原特异性Tregs的特征：Rag23 - 3和RagD10小鼠（分别是OVA23 - 3和DO11.10与Rag2基因敲除小鼠杂交）。RagD10是一个耐受模型，而Rag23 - 3在喂食蛋清（EW）时表现出严重过敏。为检测CD4⁺T细胞向Foxp3⁺Tregs（诱导性Tregs；iTregs）的分化情况，将来自肠系膜淋巴结或脾脏的CD4⁺T细胞或全细胞在Treg极化条件下培养，并用抗CD3和抗CD28抗体组合或OVA加抗原呈递细胞刺激。用抗体刺激后，未处理的Rag23 - 3和RagD10小鼠的CD4⁺T细胞诱导产生iTregs的水平相当。将未处理的Rag23 - 3小鼠产生的iTregs转移可抑制喂食EW的Rag23 - 3小鼠的过敏反应。相比之下，用OVA加抗原呈递细胞刺激可阻止未处理的Rag23 - 3小鼠的CD4⁺T细胞分化为iTregs，这表明OVA诱导的T细胞受体信号传导抑制了有效的Treg分化。此外，表示介导的分化使从喂食EW的Rag - 23 - 3小鼠肠系膜淋巴结分离的初始（CD44loCD62Lhi）CD4⁺T细胞分化为iTregs的能力明显高于效应/效应记忆（CD44hiCD62Llo）T细胞。喂食EW的Rag23 - 3小鼠的CD4⁺T细胞过度产生白细胞介素 - 4和干扰素 - γ显著抑制了RagD10小鼠中Treg的诱导，这表明严重过敏的细胞因子环境可能阻止了它们的分化。然而，我们的研究表明，即使在严重过敏的小鼠中，也可从肠道免疫系统的初始CD4⁺T细胞中获得具有调节活性的过敏原特异性Tregs。
Sci Rep. 2021-5-18
Arch Pediatr. 2021-5
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