Regulatory role of PI16 in autoimmune arthritis and intestinal inflammation: implications for Treg cell differentiation and function

• Published in: Journal of translational medicine 2024-04, Vol.22 (1), p.327-14, Article 327
• Main Authors: Sun, Yuankai, Lin, Shiyu, Wang, Hui, Wang, Lei, Qiu, Yulu, Zhang, Feifei, Hao, Nannan, Wang, Fang, Tan, Wenfeng
• Format: Article
• Language: English
• Subjects: AIA; Animals; Antibodies; Antigen-presenting cells; Antigens; Arthritis; Arthritis - metabolism; Arthritis - pathology; Autoimmune disease; Autoimmune diseases; Autoimmune Diseases - metabolism; Autoimmunity; Care and treatment; CD25 antigen; CD4 antigen; Cell Differentiation; Cell proliferation; Cells; Colitis; Colitis - chemically induced; Colitis - pathology; Cytokines; Dextran; Dextran sulfate; Dextran Sulfate - adverse effects; Diabetes; Diagnosis; DSS-induced colitis; Effector cells; Enteritis; Flow cytometry; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Foxp3 protein; Gene deletion; Genotypes; Health aspects; Helper cells; Homeostasis; Immunoregulation; Inflammation; Inflammation - pathology; Inflammatory bowel disease; Inflammatory diseases; Intestine; Lymphatic system; Lymphocytes; Lymphocytes T; Medical research; Metabolism; Mice; Mice, Inbred C57BL; PI16; Proteins; Rheumatoid arthritis; Spleen; T-Lymphocytes, Regulatory; Th17 Cells; Transcription factors; Treg; Treg/Th17 balance; Ulcerative colitis
• ISSN: 1479-5876; 1479-5876
• DOI: 10.1186/s12967-024-05082-1

Regulatory T cells (Tregs) are crucial in maintaining immune homeostasis and preventing autoimmunity and inflammation. A proportion of Treg cells can lose Foxp3 expression and become unstable under inflammation conditions. The precise mechanisms underlying this phenomenon remain unclear. The PI16 gene knockout mice (PI16 Foxp3 ) in Treg were constructed, and the genotypes were identified. The proportion and phenotypic differences of immune cells in 8-week-old mice were detected by cell counter and flow cytometry. Two groups of mouse Naïve CD4 T cells were induced to differentiate into iTreg cells to observe the effect of PI16 on the differentiation and proliferation of iTreg cells, CD4 CD25 Treg and CD4 CD25 effector T cells (Teff) were selected and co-cultured with antigen presenting cells (APC) to observe the effect of PI16 on the inhibitory ability of Treg cells in vitro. The effects of directed knockout of PI16 in Treg cells on inflammatory symptoms, histopathological changes and immune cell expression in mice with enteritis and autoimmune arthritis were observed by constructing the model of antigen-induced arthritis (AIA) and colitis induced by dextran sulfate sodium salt (DSS). We identified peptidase inhibitor 16 (PI16) as a negative regulator of Treg cells. Our findings demonstrate that conditional knock-out of PI16 in Tregs significantly enhances their differentiation and suppressive functions. The conditional knockout of the PI16 gene resulted in a significantly higher abundance of Foxp3 expression (35.12 ± 5.71% vs. 20.00 ± 1.61%, p = 0.034) in iTreg cells induced in vitro compared to wild-type mice. Mice with Treg cell-specific PI16 ablation are protected from autoimmune arthritis (AIA) and dextran sulfate sodium (DSS)-induced colitis development. The AIA model of PI16 is characterized by the reduction of joint structure and the attenuation of synovial inflammation and in DSS-induced colitis model, conditional knockout of the PI16 reduce intestinal structural damage. Additionally, we found that the deletion of the PI16 gene in Treg can increase the proportion of Treg (1.46 ± 0.14% vs. 0.64 ± 0.07%, p