DataSheet_3_Transcriptional re-programming of insulin B-chain epitope-specific T-follicular helper cells into anti-diabetogenic T-regulatory type-1 cells.xlsx

Systemic delivery of nanoparticles (NPs) coated with mono-specific autoimmune disease-relevant peptide-major histocompatibility complex class II (pMHCII) molecules can resolve organ inflammation in various disease models in a disease-specific manner without impairing normal immunity. These compounds invariably trigger the formation and systemic expansion of cognate pMHCII-specific T-regulatory type 1 (TR1) cells. By focusing on type 1 diabetes (T1D)-relevant pMHCII-NP types that display an epitope from the insulin B-chain bound to the same MHCII molecule (IAg7) on three different registers, we show that pMHCII-NP-induced TR1 cells invariably co-exist with cognate T-Follicular Helper (TFH)-like cells of quasi-identical clonotypic composition and are oligoclonal, yet transcriptionally homogeneous. Furthermore, these three different TR1 specificities have similar diabetes reversal properties in vivo despite being uniquely reactive against the peptide MHCII-binding register displayed on the NPs. Thus, pMHCII-NP treatment using nanomedicines displaying different epitope specificities results in the simultaneous differentiation of multiple antigen-specific TFH-like cell clones into TR1-like cells that inherit the fine antigenic specificity of their precursors while acquiring a defined transcriptional immunoregulatory program.

以单一特异性自身免疫疾病相关肽-主要组织相容性复合体II类（peptide-major histocompatibility complex class II, pMHCII）分子包被的纳米颗粒（nanoparticles, NPs）经系统给药后，可在不损害正常免疫功能的前提下，以疾病特异性方式缓解多种疾病模型中的器官炎症。此类制剂始终可触发同源pMHCII特异性1型调节性T细胞（T-regulatory type 1, TR1）的形成与全身性扩增。本研究聚焦于1型糖尿病（type 1 diabetes, T1D）相关的pMHCII-NP制剂：此类制剂展示了以三种不同结合取向结合于同一MHCII分子（IAg7）的胰岛素B链表位。研究结果显示，pMHCII-NP诱导产生的TR1细胞始终与克隆型组成近乎一致的同源滤泡辅助性T细胞（T-Follicular Helper, TFH）样细胞共存，且这些TR1细胞呈寡克隆状态，但转录组特征均一。此外，尽管这三种不同的TR1细胞特异性仅分别识别纳米颗粒上展示的对应pMHCII结合取向，它们在体内均展现出相似的糖尿病逆转效果。综上，使用展示不同表位特异性纳米药物开展的pMHCII-NP治疗，可同时将多种抗原特异性TFH样细胞克隆分化为TR1样细胞；此类子代细胞既继承了前体细胞精细的抗原识别特异性，又获得了一套明确的转录组免疫调节程序。