Functional Analysis of CBAP in T Cell Development
Date Issued
2014
Date
2014
Author(s)
Ho, Kun-Chin
Abstract
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. Our laboratory previously demonstrated that GM-CSF/IL-3/IL-5 receptor common β-chain associated protein (CBAP) modulates cytokine withdrawal-induced apoptosis in vitro and ZAP70-mediated T cell migration/adhesion in vivo. In this study, the function of CBAP in T cell lineage was further investigated. Based on the high expression of CBAP during thymocyte development, a CBAP knockout mouse was utilized to investigate the function of CBAP in thymocyte development. 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. Furthur investigation on TCR proximal signaling revealed that TCR-induced association of LAT signalosome components is reduced in CBAP-deficient thymocytes. These data demonstrate that CBAP is a novel component in the TCR signaling pathway and modulates thymocyte apoptosis during negative selection. Moreover, CBAP-interacting proteins identified by a yeast two-hybrid system implied that CBAP is involved in divergent biological processes, echoing multiple functions of CBAP characterized in the previous and present studies.
Subjects
T cell development
negative selection
TCR signaling
Type
thesis
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