CBAP promotes thymocyte negative selection by facilitating T-cell receptor proximal signaling.
T-cell receptor (TCR)-transduced signaling is critical to thymocyte development at the CD4/CD8 double-positive stage, but the molecules involved in this process are not yet fully characterized. We previously demonstrated that GM-CSF/IL-3/IL-5 receptor common β-chain-associated protein (CBAP) modulates ZAP70-mediated T-cell migration and adhesion. On the basis of the high expression of CBAP during thymocyte development, we investigated the function of CBAP in thymocyte development using a CBAP knockout mouse. CBAP-deficient mice showed normal early thymocyte development and positive selection. In contrast, several negative selection models (including TCR transgene, superantigen staphylococcal enterotoxin B, and anti-CD3 antibody treatment) revealed an attenuation of TCR-induced thymocyte deletion in CBAP knockout mice. This phenotype correlated with a reduced accumulation of BIM upon TCR crosslinking in CBAP-deficient thymocytes. Loss of CBAP led to reduced TCR-induced phosphorylation of proteins involved in both proximal and distal signaling events, including ZAP70, LAT, PLCγ1, and JNK1/2. Moreover, TCR-induced association of LAT signalosome components was reduced in CBAP-deficient thymocytes. Our data demonstrate that CBAP is a novel component in the TCR signaling pathway and modulates thymocyte apoptosis during negative selection.
1] Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan [2] Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
K-C
KC
Ho
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
Y-J
YJ
Chiang
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
A C-Y
AC
Lai
Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan.
N-S
NS
Liao
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
Y-J
YJ
Chang
Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan.
H-F
HF
Yang-Yen
1] Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan [2] Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
J J-Y
JJ
Yen
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D002448:Cell Adhesion; D002454:Cell Differentiation; D002465:Cell Movement; D005260:Female; D018507:Gene Expression Regulation, Developmental; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D048055:Mitogen-Activated Protein Kinase 8 / Q000235:genetics / Q000378:metabolism; D048056:Mitogen-Activated Protein Kinase 9 / Q000235:genetics / Q000378:metabolism; D051966:Phospholipase C gamma / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D060168:Thymocytes / Q000166:cytology / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C491734:Lat protein, mouse; D008565:Membrane Proteins; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D011948:Receptors, Antigen, T-Cell; C584198:TMEM102 protein, mouse; D048056:Mitogen-Activated Protein Kinase 9; D051746:ZAP-70 Protein-Tyrosine Kinase; C497262:Zap70 protein, mouse; D048055:Mitogen-Activated Protein Kinase 8; D051966:Phospholipase C gamma