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Title: The phosphatase JKAP/DUSP22 inhibits t-cell receptor signalling and autoimmunity by inactivating Lck

Author
item LI, JU-PI - National Health Research Institutes
item YANG, CHIA-YU - National Health Research Institutes
item LAN, JOUNG-LIANG - China Medical University
item WANG, XIAOHONG - Baylor College Of Medicine
item CHEN, ALICE - Baylor College Of Medicine
item BELMONT, JOHN - Children'S Nutrition Research Center (CNRC)
item TAN, TSE-HUA - National Health Research Institutes

Submitted to: Nature Communications
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/11/2014
Publication Date: 4/9/2014
Citation: Li, J., Yang, C., Lan, J., Wang, X., Chen, A.J., Belmont, J.W., Tan, T. 2014. The phosphatase JKAP/DUSP22 inhibits t-cell receptor signalling and autoimmunity by inactivating Lck. Nature Communications. 5:3618.

Interpretive Summary: The immune system has many types of cells that provide defense against infection. Some common diseases, like arthritis and diabetes, are caused by the immune system attacking normal cells in the body. The T cells are one of the most important groups of immune cells. They have a system to control their responses. We found that JKAP, an enzyme that regulates the attachment of phosphorus to proteins, is an important part of the mechanism to control the T cell response and to turn it off after it has been activated. Mice that lack JKAP develop health problems that mimic common immune problems in older people. Nutritional factors are known to affect the immune system. Nutritional deficiencies lead to increased susceptibility to infections and decreased response to vaccines. This study fills a gap in understanding how the immune system regulates itself and identifies one of the steps in the immune response that may affected by nutrition.

Technical Abstract: JNK pathway-associated phosphatase (JKAP, also known as DUSP22 or JSP-1) is a JNK activator. The in vivo role of JKAP in immune regulation remains unclear. Here we report that JKAP directly inactivates Lck by dephosphorylating tyrosine-394 residue during T-cell receptor (TCR) signalling. JKAP-knockout T cells display enhanced cell proliferation and cytokine production. JKAP-knockout mice show enhanced T-cell-mediated immune responses and are more susceptible to experimental autoimmune encephalomyelitis (EAE). In addition, the recipient mice that are adoptively transferred with JKAP-knockout T cells show exacerbated EAE symptoms. Aged JKAP-knockout mice spontaneously develop inflammation and autoimmunity. Thus, our results indicate that JKAP is an important phosphatase that inactivates Lck in the TCR signalling turn-off stage, leading to suppression of T-cell-mediated immunity and autoimmunity.