The phosphatase JKAP/DUSP22 inhibits T-cell receptor signalling and autoimmunity by inactivating Lck.
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.
Immunology Research Center, National Health Research Institutes, Zhunan 35053, Taiwan.
Ju-Pi
JP
Li
1] Immunology Research Center, National Health Research Institutes, Zhunan 35053, Taiwan [2].
Chia-Yu
CY
Yang
1] Immunology Research Center, National Health Research Institutes, Zhunan 35053, Taiwan [2].
Huai-Chia
HC
Chuang
1] Division of Allergy, Immunology, and Rheumatology, Taichung Veterans General Hospital, Taichung 40705, Taiwan [2] Department of Medicine, China Medical University, Taichung 40402, Taiwan [3] Division of Rheumatology & Immunology, Department of Internal Medicine, China Medical University Hospital, Taichung 40402, Taiwan [4].
Joung-Liang
JL
Lan
1] Division of Allergy, Immunology, and Rheumatology, Taichung Veterans General Hospital, Taichung 40705, Taiwan [2] Faculty of Medicine, National Yang-Ming University, Taipei 11221, Taiwan [3].
Der-Yuan
DY
Chen
1] Division of Allergy, Immunology, and Rheumatology, Taichung Veterans General Hospital, Taichung 40705, Taiwan [2] Faculty of Medicine, National Yang-Ming University, Taipei 11221, Taiwan [3].
Yi-Ming
YM
Chen
Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030, USA.
Xiaohong
X
Wang
1] Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030, USA [2] Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
Alice J
AJ
Chen
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
John W
JW
Belmont
1] Immunology Research Center, National Health Research Institutes, Zhunan 35053, Taiwan [2] Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030, USA.
Tse-Hua
TH
Tan
D000818:Animals; D006801:Humans; D051379:Mice; D015551:Autoimmunity / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D003720:Densitometry; D054637:Dual-Specificity Phosphatases / Q000235:genetics / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D015151:Immunoblotting; D047468:Immunoprecipitation; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
D054637:Dual-Specificity Phosphatases; C522152:Dusp22 protein, mouse; D010749:Phosphoprotein Phosphatases