Partially exhausted CD8+ T cells are associated with clinically beneficial response to Teplizumab in new onset type I diabetes (bulk RNA-seq of sorted CD8+ T-cells). Homo sapiens

Biologic agents active in other autoimmune settings have had variable effectiveness in newly diagnosed type 1 diabetes (T1D) where treatment across therapeutic targets is accompanied by transient stabilization of C-peptide levels in some patients, followed by progression at the same rate as in control groups. Why disparate treatments lead to similar clinical courses is currently unknown. Here, we use integrated systems biology and flow cytometry approaches to elucidate immunologic mechanisms associated with C-peptide stabilization in T1D subjects treated with the anti-CD3 monoclonal antibody, teplizumab. This work is part of the Immune Tolerance Network AbATE study (Autoimmunity-Blocking Antibody for Tolerance in Recently Diagnosed Type 1 Diabetes); data are also available through the ITN TrialShare portal: https://www.itntrialshare.org/project/Studies/ITN027AIDB/Study%20Data/begin.view?. Overall design: We performed bulk RNA-seq on 63 sorted CD8+ T-cell samples from 3 responders at visit month 6 (N = 34, 15, 14); we sorted cells with and without EOMES-associated inhibitory receptors (TIGIT, KLRG1); prior to RNA extraction, cells were either unstimulated, stimulated with anti-CD3 and anti-CD28, or stimulated with additional PVR-Fc treatment.

在其他自身免疫疾病场景中展现活性的生物制剂，在新诊断1型糖尿病（T1D）患者中疗效参差不齐：针对治疗靶点的此类治疗仅能使部分患者的C肽水平出现暂时性稳定，后续患者的疾病进展速率仍与对照组保持一致。目前尚不明确为何不同的治疗方案会带来相似的临床转归。本研究通过整合系统生物学（integrated systems biology）与流式细胞术（flow cytometry）方法，旨在阐明接受抗CD3单克隆抗体（anti-CD3 monoclonal antibody）替利单抗（teplizumab）治疗的T1D患者中，与C肽水平稳定相关的免疫机制。本研究隶属于免疫耐受网络（Immune Tolerance Network，ITN）AbATE研究（Autoimmunity-Blocking Antibody for Tolerance in Recently Diagnosed Type 1 Diabetes，新诊断1型糖尿病自身免疫阻断抗体诱导耐受研究）；相关数据可通过ITN试验共享门户（ITN TrialShare portal）获取，链接为：https://www.itntrialshare.org/project/Studies/ITN027AIDB/Study%20Data/begin.view?。研究设计：我们对3名治疗应答者在第6次随访时获取的63份分选CD8+ T细胞样本进行了批量RNA测序（bulk RNA-seq），样本量分别为34、15、14；我们分选了表达EOMES相关抑制性受体（TIGIT、KLRG1）与不表达该类受体的细胞；在RNA提取前，细胞分别接受未刺激、抗CD3与抗CD28刺激，或额外施加PVR-Fc刺激处理。