An altered CD8~+ T cell epitope of insulin prevents type 1 diabetes in humanized NOD mice
An altered CD8~+ T cell epitope of insulin prevents type 1 diabetes in humanized NOD mice
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改变的胰岛素 CD8~ T 细胞表位可预防人源化 NOD 小鼠的 1 型糖尿病
DOI：
10.1038/s41423-018-0058-3
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发表时间：
2018
影响因子：
24.1
通讯作者：
Wang Li
中科院分区：
文献类型：
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作者：
Zhang Mengjun;Wang Shufeng;Guo Binbin;Meng Gang;Shu Chi;Mai Wenli;Zheng Qian;Chen Xiaoling;Wu Yuzhang;Wang Li
自身反应性CD8+T细胞在β细胞破坏中起着不可或缺的作用，是预防1型糖尿病(T1D)的新靶点。改变的多肽配体(APL)可以有效地诱导抗原特异性T细胞无能、细胞凋亡或免疫应答的改变。在此，我们发现HLAA0201限制性T细胞对β细胞自身抗原胰岛素表位InsB15-14的反应存在于NOD、β2null.HHD NOD小鼠和T1D患者中。我们通过p6位的残基替换产生了几个InsB15-14的APL候选基因。只有H6F在体外对mInsB15-14特异性CD8~+T细胞反应有抑制作用。H6F治疗可显著降低NOD-β2ml.HHD小鼠T1D的发生率，同时伴有CD8+T细胞对mInsB15-14的自身反应性减弱，抑制CD8+和CD4+T细胞在胰腺中的渗透，减少胰腺和脾T细胞的促炎细胞因子的产生。从机制上讲，H6F能显著增加小鼠脾中CD8~+CD25~+Foxp3~+T细胞的数量，尤其是胰腺中的CD8~+CD25~+Foxp3~+T细胞。这一亚群表现出典型的Treg表型，需要多肽特异性的再刺激才能发挥免疫抑制活性。因此，APL H6F在抗原特异性预防T1D方面具有潜在的临床应用价值。
Autoreactive CD8~+ T cells, which play an indispensable role in β cell destruction, represent an emerging target for the prevention of type 1 diabetes (T1D). Altered peptide ligands (APLs) can efficiently induce antigen-specific T cells anergy, apoptosis or shifts in the immune response. Here, we found that HLA-A*0201-restricted CD8~+ T cell responses against a primary β-cell autoantigen insulin epitope InsB15-14 were present in both NOD.β2mnull.HHD NOD mice and T1D patients. We generated several APL candidates for InsB15-14 by residue substitution at the p6 position. Only H6F exhibited an inhibitory effect on mInsB15-14-specific CD8~+ T cell responses in vitro. H6F treatment significantly reduced the T1D incidence, which was accompanied by diminished autoreactive CD8~+ T cell responses to mInsB15-14, inhibited infiltration of CD8~+ and CD4~+ T cells in the pancreas and reduced pro-inflammatory cytokine production in pancreatic and splenic T cells in NOD.β2mnull.HHD mice. Mechanistically, H6F treatment significantly augmented a tiny portion of CD8~+CD25~+Foxp3~+ T cells in the spleen and especially in the pancreas. This subset exhibited typical Treg phenotypes and required peptide-specific restimulation to exert immunosuppressive activity. Therefore, this APL H6F may be a promising candidate with potential clinical application value for antigen-specific prevention of T1D.