Conversion of T Follicular Helper Cells to T Follicular Regulatory Cells by Interleukin‐2 Through Transcriptional Regulation in Systemic Lupus Erythematosus

作者：Hao He, Shingo Nakayamada, Kaoru Yamagata, Naoaki Ohkubo, S. Iwata, Yoshino Inoue, Mingzeng Zhang, Tong Zhang, Yurie Satoh, Yu Shan, Takashi Otsuka, Yoshiya Tanaka · 发表于：Arthritis & Rheumatology · 年份：2020 · DOI：10.1002/art.41457 · 被引用次数：70 · 研究领域：T-cell and B-cell Immunology、Hematopoietic Stem Cell Transplantation、Systemic Lupus Erythematosus Research

Objective This study was undertaken to identify characteristics of follicular regulatory T (Tfr) cells and elucidate the mechanisms by which follicular helper T (Tfh) cells convert to Tfr cells. We probed the phenotype of T helper cells in patients with systemic lupus erythematosus (SLE) and underlying transcriptional regulation using cytokine‐induced STAT family factors. Methods Peripheral blood mononuclear cells from 41 patients with SLE and 26 healthy donors were used to sort out the memory Tfh cell subset, and Tfh cells were cultured under various conditions. The phenotype of T helper cells and underlying mechanisms of transcriptional regulation were probed using flow cytometry and quantitative polymerase chain reaction analyses. These analyses evaluated the expression of characteristic markers and phosphorylation of STATs. Chromatin immunoprecipitation was used to evaluate histone modifications. Results In patients with SLE, the proportion of CD4+CXCR5+FoxP3–PD‐1 high Tfh cells was increased ( P < 0.01), whereas the proportion of CD4+CXCR5+CD45RA–FoxP3 high activated Tfr cells was decreased ( P < 0.05). Serum interleukin‐2 (IL‐2) levels were also reduced in patients with SLE. IL‐2 induced conversion of memory Tfh cells to functional Tfr cells, which was characterized by CXCR5+Bcl‐6+FoxP3 high pSTAT3+pSTAT5+ cells. The loci of FOXP3 and BCL6 at STAT binding sites were marked by bivalent histone modifications. Following IL‐2 stimulation, STAT3 and STAT5 selectively b...