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. 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.
Highlights
Establishing tolerance to self is essential for shaping a wellfunctioning immune system, and thymic negative selection is a crucial step in this process.[9]
We investigated the function of CBAP in thymocyte development using a gene knockout (KO) strategy
Because CBAP has a pro-apoptotic function in a variety of cell lines,[16] we examined whether it is involved in apoptosis of DN thymocytes that fail to rearrange the TCRβ gene, a process that is at least partly FADDmediated.[19]
Summary
Establishing tolerance to self is essential for shaping a wellfunctioning immune system, and thymic negative selection is a crucial step in this process.[9]. Two critical substrates of ZAP70, LAT and SLP76, are activated to organize formation of the proximal signalosome, which is responsible for transducing a series of kinase cascades that in turn lead to the release of secondary messengers and activation of RAS and mitogenactivated protein kinase (MAPK) pathways.[10] In response to strong TCR signals, MAPKs are suggested to trigger death pathways mediated by the BCL-2 family member BIM and the orphan nuclear receptor NUR77, respectively.[9,11,12,13] Both BIM and NUR77 act on BCL-2,14,15 which likely results in mitochondrial dysfunction followed by thymocyte death.[9] Optimal formation and signaling of the LAT signalosome during negative selection promotes efficient elimination of thymocytes that can potentially attack the organism itself, thereby preventing the development of autoimmunity. We previously reported that GM-CSF/IL-3/IL-5 receptor common β-chain-associated protein (CBAP) plays a dual role in in vitro cell apoptosis[16] and in vivo T-cell migration and adhesion.[17] In T cells, CBAP is a component of the β1-integrin complex and is involved in ZAP70-mediated VAV1 phosphorylation. Our data suggest that CBAP is a novel component of the LAT signalosome and plays a positive role in thymocyte negative selection
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