Schroderus Anna-Mari, Hanel Andrea, Vandamme Céline, Pitkänen Viola, Rytkönen-Nissinen Marja, Heinäniemi Merja, Knip Mikael, Veijola Riitta, Toppari Jorma, Ilonen Jorma, Lempainen Johanna, Kinnunen Tuure
Department of Clinical Microbiology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
Faculty of Health Sciences, Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
Eur J Immunol. 2025 Jun;55(6):e51704. doi: 10.1002/eji.202451704.
Circulating follicular (cTfh) and peripheral (cTph) T helper cells have been demonstrated to be expanded in several autoimmune diseases, including type 1 diabetes (T1D). Here, we examined the frequencies and phenotypes of these cells at different stages of T1D development and addressed their phenotypic and clonal relationships by analyzing samples from 27 children with newly diagnosed T1D, 29 autoantibody-positive (AAb) children who later progressed to T1D and 57 healthy, age-matched controls. Higher frequencies of cTph cells were detected in children with T1D and AAb children by flow cytometry, but no phenotypic alterations compared with cTph cells from healthy children were observed. Through a single-cell multiomics approach, we demonstrate that cTph cells appear phenotypically more heterogeneous compared with cTfh cells and that they exhibit phenotypic and clonal sharing with both cTfh as well as CXCR5PD-1 memory T cells. Finally, the frequencies of cTph or cTfh cells did not differ in 17 children analyzed during seroconversion for T1D-associated autoantibodies, the earliest detectable time point for autoimmunity. Collectively, our data demonstrate that cTph cells are a highly heterogeneous population partially sharing features with cTfh cells and that their frequency but not phenotype is altered at later stages of progression to clinical T1D.
循环滤泡辅助性T细胞（cTfh）和外周辅助性T细胞（cTph）已被证明在包括1型糖尿病（T1D）在内的多种自身免疫性疾病中有所扩增。在此，我们检测了T1D发展不同阶段这些细胞的频率和表型，并通过分析27例新诊断T1D患儿、29例后来进展为T1D的自身抗体阳性（AAb）患儿以及57例年龄匹配的健康对照的样本，探讨了它们的表型和克隆关系。通过流式细胞术在T1D患儿和AAb患儿中检测到更高频率的cTph细胞，但与健康儿童的cTph细胞相比未观察到表型改变。通过单细胞多组学方法，我们证明与cTfh细胞相比，cTph细胞在表型上显得更加异质性，并且它们与cTfh细胞以及CXCR5⁺PD-1记忆T细胞表现出表型和克隆共享。最后，在17例T1D相关自身抗体血清转化期间（自身免疫最早可检测时间点）进行分析的儿童中，cTph或cTfh细胞的频率没有差异。总体而言，我们的数据表明cTph细胞是一个高度异质性群体，部分与cTfh细胞共享特征，并且在进展至临床T1D的后期阶段其频率而非表型发生改变。
