ITK signalling via the Ras/IRF4 pathway regulates the development and function of Tr1 cells

• Published in: Nature communications Vol. 8; no. 1; pp. 15871 - 15
• Main Authors: Huang, Weishan, Solouki, Sabrina, Koylass, Nicholas, Zheng, Song-Guo, August, Avery
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21-06-2017; Nature Publishing Group; Nature Portfolio
• Subjects: 631/250/1619/554/1775; 631/250/1619/554/1898/1271; Animals; Cell Differentiation; Cytokines; Differentiation (biology); Foxp3 protein; Functional anatomy; Humanities and Social Sciences; Humans; Immunological tolerance; Immunosuppression; Interferon; Interferon regulatory factor; Interferon regulatory factor 4; Interferon Regulatory Factors - genetics; Interferon Regulatory Factors - metabolism; Interleukin 10; Itk protein; Kinases; Lymphocytes; Lymphocytes T; Mice, Inbred C57BL; Mice, Transgenic; Mucosa; multidisciplinary; Organs; Orthomyxoviridae Infections - immunology; Positive Regulatory Domain I-Binding Factor 1 - metabolism; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; ras Proteins - genetics; ras Proteins - metabolism; Science; Signal Transduction; Signaling; Strongylida Infections - immunology; T cell receptors; T-Lymphocytes, Regulatory - cytology; T-Lymphocytes, Regulatory - metabolism; T-Lymphocytes, Regulatory - physiology
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms15871

Type 1 regulatory T (Tr1) cells differentiate in response to signals engaging the T cell receptor (TCR), express high levels of the immunosuppressive cytokine IL-10, but not Foxp3, and can suppress inflammation and promote immune tolerance. Here we show that ITK, an important modulator of TCR signalling, is required for the TCR-induced development of Tr1 cells in various organs, and in the mucosal system during parasitic and viral infections. ITK kinase activity is required for mouse and human Tr1 cell differentiation. Tr1 cell development and suppressive function of
Itk
deficient cells can be restored by the expression of the transcription factor interferon regulatory factor 4 (IRF4). Downstream of ITK, Ras activity is responsible for Tr1 cell induction, as expression of constitutively active HRas rescues IRF4 expression and Tr1 cell differentiation in
Itk
−/−
cells. We conclude that TCR/ITK signalling through the Ras/IRF4 pathway is required for functional development of Tr1 cells.
IL-10
+
Tr1 cells, which do not express stable Foxp3 like conventional Treg cells, are associated with various diseases, but little is known about how their differentiation and function are regulated. Here the authors show that ITK is a central TCR signalling effector of the differentiation and function of Tr1 cells.