Ssu72 is a T-cell receptor-responsive modifier that is indispensable for regulatory T cells

• Published in: Cellular & molecular immunology Vol. 18; no. 6; pp. 1395 - 1411
• Main Authors: Lee, Jin-Kwan, Koo, Seo-Young, Nam, Hye-Mi, Lee, Jee-Boong, Ko, Jiwon, Kim, Kyung-Mo, Park, Eun-Ji, Kim, Tae Jin, Lee, Ho, Go, Heounjeong, Lee, Chang-Woo
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-06-2021; Nature Publishing Group
• Subjects: 631/250/38; 631/250/516; Adaptive immunity; Animals; Antibodies; Biomedical and Life Sciences; Biomedicine; CD4 antigen; Cell activation; Cell Differentiation; Cell Lineage; Cell membranes; Clonal deletion; Disease Susceptibility; Effector cells; Epigenetics; Forkhead Transcription Factors - metabolism; Foxp3 protein; Homeostasis; Immune Tolerance; Immunological tolerance; Immunology; Immunoregulation; Inflammatory Bowel Diseases - immunology; Inflammatory Bowel Diseases - pathology; Interleukin 2; Interleukin 2 receptors; Lymphocytes; Lymphocytes T; Medical Microbiology; Mice; Mice, Inbred C57BL; Mice, Knockout; Microbiology; Models, Biological; Mucosa; Nuclear Receptor Subfamily 1, Group F, Member 3 - metabolism; Phospholipase C gamma - metabolism; Phosphoprotein Phosphatases - deficiency; Phosphoprotein Phosphatases - metabolism; Phosphorylation; Protein Binding; Receptors, Antigen, T-Cell - metabolism; Signal Transduction; T cell receptors; T-Lymphocytes, Regulatory - immunology; Vaccine; γ-Interferon; Autoimmunity; T cell receptor; Regulatory T cells; FoxP3; Ssu72
• ISSN: 1672-7681; 2042-0226
• DOI: 10.1038/s41423-021-00671-2

The homeostatic balance between effector T cells and regulatory T cells (Tregs) is crucial for adaptive immunity; however, epigenetic programs that inhibit phosphorylation to regulate Treg development, peripheral expression, and suppressive activity are elusive. Here, we found that the Ssu72 phosphatase is activated by various T-cell receptor signaling pathways, including the T-cell receptor and IL-2R pathways, and localizes at the cell membrane. Deletion of Ssu72 in T cells disrupts CD4
+
T-cell differentiation into Tregs in the periphery via the production of high levels of the effector cytokines IL-2 and IFNγ, which induce CD4
+
T-cell activation and differentiation into effector cell lineages. We also found a close correlation between downregulation of Ssu72 and severe defects in mucosal tolerance in patients. Interestingly, Ssu72 forms a complex with PLCγ1, which is an essential effector molecule for T-cell receptor signaling as well as Treg development and function. Ssu72 deficiency impairs PLCγ1 downstream signaling and results in failure of Foxp3 induction. Thus, our studies show that the Ssu72-mediated cytokine response coordinates the differentiation and function of Treg cells in the periphery.