CD4+ T cell plasticity plays a pivotal role in immune homeostasis. However, evidence of T cell plasticity and its pathological role in human systemic lupus erythematosus (SLE) is missing due to the lack of a reporter system. Here we utilized T cell receptor (TCR) repertoire data as a molecular signatures alongside transcriptomic dataset. Using a large-scale ImmuNexUT database of autoimmune disease patients including 117 SLE cases, we quantified T cell plasticity across 13 fine-grained T cell-types. We analyzed 6,392 samples in total and identified two orthogonal signatures of repertoire and transcriptome, the cell-type and disease signatures, allowing us to investigate CD4+ T cell plasticity comprehensively. Among all possible patterns, the plasticity level was the highest in effector regulatory T cells (eTreg) to Th1 plasticity, which was replicated in an independent cohort. Moreover, eTreg-to-Th1 plasticity positively correlated with SLE disease activity. Our study provides novel evidence that Treg plasticity is involved in SLE pathology.

Y.N., M.Ota., T.I., and T.O. belonged to the Social Cooperation Program, Department of functional genomics and immunological diseases, supported by Chugai Pharmaceutical. K.K. receives speaking fees from Chugai Pharmaceutical.

This research was supported by the Japan Agency for Medical Research and Development (AMED) (JP21tm0424221, JP21zf0127004, JP22ek0410074, JP223fa627001, JP233fa627001, JP23gm1810005, JP22tm0424223, JP22ek0410099, and JP23tm0524005), the Center of Innovation Program from Japan Science and Technology Agency (JST) (JPMJCE1304), JSPS KAKENHI (22K08538, JP19H03697, and JP22H03110), the Uehara Memorial Foundation, and Chugai Pharmaceutical Co., Ltd., Tokyo, Japan.

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This study was approved by the Ethics Committees of the University of Tokyo (G-10095).

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