Treg-Specific CD226 Deletion Reduces Diabetes Incidence in NOD Mice by Improving Regulatory T-Cell Stability.
Treg-Specific CD226 Deletion Reduces Diabetes Incidence in NOD Mice by Improving Regulatory T-Cell Stability.
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Treg特异性CD226缺失通过提高调节性T细胞稳定性来降低NOD小鼠的糖尿病发生率。
DOI：
10.2337/db23-0307
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发表时间：
2023-11-01
期刊：
影响因子：
7.7
通讯作者：
Brusko, Todd M.
中科院分区：
文献类型：
--
作者：
Thirawatananond, Puchong;Brown, Matthew E.;Sachs, Lindsey K.;Arnoletti, Juan M.;Yeh, Wen-I;Posgai, Amanda L.;Shapiro, Melanie R.;Chen, Yi-Guang;Brusko, Todd M.
共刺激作为T细胞活化的关键检查点，并且影响共刺激通路的几种遗传变异赋予自身免疫性疾病的风险。编码共刺激受体的CD 226基因的单核苷酸多态性（rs763361）增加了对多种自身免疫性疾病（包括1型糖尿病）的易感性。我们以前发现，CD 226基因敲除保护NOD小鼠免受疾病的影响，但CD 226对个体免疫亚群的影响仍不清楚。我们先前的报道涉及调节性T细胞（TCLs），因为人CD 226 + TCLs表现出降低的抑制功能。因此，我们假设基因组Cd 226基因缺失会增加Treg的稳定性，Treg特异性Cd 226缺失会抑制NOD小鼠的糖尿病。事实上，交叉NOD.Cd226−/−和NOD Treg谱系追踪菌株导致胰腺Foxp 3缺陷型“前TdR”减少。我们产生了一种新的Treg条件性敲除（TregΔ Cd 226）菌株，该菌株显示胰岛炎和糖尿病发病率降低。CD 226缺陷型胰腺TCLs增加了具有IG和基于免疫受体酪氨酸的抑制性基序结构域（TIGIT）的共抑制性反受体T细胞免疫受体的表达。此外，用TIGIT-Fc融合蛋白处理的NOD脾细胞在抗⑶ 3/⑶ 28刺激后表现出降低的T细胞增殖和干扰素-γ产生。这项研究表明，CD 226/TIGIT失衡导致NOD小鼠中的Treg不稳定性，并强调了靶向这种共刺激途径的治疗剂阻止自身免疫的潜力。我们以前发现，Cd 226基因敲除（gKO）在NOD小鼠胰岛炎的严重程度和糖尿病的发病率降低，但对个别免疫亚群的影响仍不清楚。人CD 226+调节性T细胞（TcM）表现出降低的抑制功能，表明Cd 226 gKO将增加Treg稳定性，并且Treg特异性Cd 226缺失将抑制NOD小鼠中的糖尿病。Treg-条件性Cd 226 KO减少了雌性NOD小鼠的胰岛炎并延迟了糖尿病发作，而Cd 226 gKO NOD小鼠显示胰腺中Foxp 3缺陷型TCLs减少，TCLs上具有IG的T细胞免疫受体和基于免疫受体酪氨酸的抑制性基序结构域（TIGIT）表达增加。CD 226/TIGIT失衡导致NOD小鼠中的Treg不稳定性，并突出了在1型糖尿病中靶向这种共刺激途径的治疗潜力。
Costimulation serves as a critical checkpoint for T-cell activation, and several genetic variants affecting costimulatory pathways confer risk for autoimmune diseases. A single nucleotide polymorphism (rs763361) in the CD226 gene encoding a costimulatory receptor increases susceptibility to multiple autoimmune diseases, including type 1 diabetes. We previously found that Cd226 knockout protected NOD mice from disease, but the impact of CD226 on individual immune subsets remained unclear. Our prior reports implicate regulatory T cells (Tregs), as human CD226+ Tregs exhibit reduced suppressive function. Hence, we hypothesized that genomic Cd226 gene deletion would increase Treg stability and that Treg-specific Cd226 deletion would inhibit diabetes in NOD mice. Indeed, crossing NOD.Cd226−/− and a NOD Treg-lineage tracing strain resulted in decreased pancreatic Foxp3-deficient “ex-Tregs.” We generated a novel Treg-conditional knockout (TregΔCd226) strain that displayed decreased insulitis and diabetes incidence. CD226-deficient pancreatic Tregs had increased expression of the coinhibitory counter-receptor T-cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT). Moreover, NOD splenocytes treated with TIGIT-Fc fusion protein exhibited reduced T-cell proliferation and interferon-γ production following anti-CD3/CD28 stimulation. This study demonstrates that a CD226/TIGIT imbalance contributes to Treg instability in NOD mice and highlights the potential for therapeutic targeting this costimulatory pathway to halt autoimmunity. We previously found that Cd226 genomic knockout (gKO) in NOD mice reduced insulitis severity and diabetes incidence, but the impact on individual immune subsets remained unclear. Human CD226+ regulatory T cells (Tregs) exhibit reduced suppressive function, suggesting Cd226 gKO would increase Treg stability, and Treg-specific Cd226 deletion would inhibit diabetes in NOD mice. Treg-conditional Cd226 KO reduced insulitis and delayed diabetes onset in female NOD mice, while Cd226 gKO NOD mice displayed reduced Foxp3-deficient Tregs in pancreas and increased T-cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) expression on Tregs. CD226/TIGIT imbalance contributes to Treg instability in NOD mice and highlights the potential for therapeutic targeting this costimulatory pathway in type 1 diabetes.
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4.2
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