Abstract
OCILRP2 is a typical Type-II transmembrane protein that is selectively expressed in activated T lymphocytes, dendritic cells, and B cells and functions as a novel co-stimulator of T cell activation. However, the signaling pathways underlying OCILRP2 in T cell activation are still not completely understood. In this study, we found that the knockdown of OCILRP2 expression with shRNA or the blockage of its activity by an anti-OCILRP2 antagonist antibody reduced CD3/CD28-costimulated EL4 T cell viability and IL-2 production, inhibit Raf1, MAPK3, and MAPK8 activation, and impair NFAT and NF-κB transcriptional activities. Furthermore, immunoprecipitation results indicated that OCILRP2 could interact with the DAP12 protein, an adaptor containing an intracellular ITAM motif that can transduce signals to induce MAP kinase activation for T cell activation. Our data reveal that after binding with DAP12, OCILRP2 activates the Raf-MAP kinase pathways, resulting in T cell activation.
Highlights
T cell activation is tightly regulated by an intricate series of signals provided by the T cell receptor/CD3 complex, cytokines, and co-stimulatory ligand/receptor systems
The intracellular domain of OCILRP2 lacks the immunoreceptor tyrosine-based activation motif (ITAM) that triggers lymphocyte activation, suggesting that OCILRP2 may transmit co-stimulatory signal via adaptors, such as DAP12 [4,5], which interacts with NKG2D in activated NK cells and CD8+ T cells [6]
We confirmed that OCILRP2 co-stimulates T cell activation in mouse EL4 cells, and for the first time, we identify that an adaptor protein, DAP12, interacts with OCILRP2 and is involved in this T cell activation
Summary
T cell activation is tightly regulated by an intricate series of signals provided by the T cell receptor/CD3 complex, cytokines, and co-stimulatory ligand/receptor systems. The intracellular domain of OCILRP2 lacks the immunoreceptor tyrosine-based activation motif (ITAM) that triggers lymphocyte activation, suggesting that OCILRP2 may transmit co-stimulatory signal via adaptors, such as DAP12 [4,5], which interacts with NKG2D (natural killer group 2, member D) in activated NK cells and CD8+ T cells [6]. DAP12 most likely activates SHC (Src homology 2 domain containing) transforming protein 1 via the Syk-family protein-tyrosine kinase Zap-70 [7,8]. The sequential phosphorylation of the adaptors further triggers downstream signaling events, including the activation of the MAP and JNK kinases and nuclear translocation of transcription factors NF-AT [9], NF-kB [10], and AP-1 [11], leading to IL-2 gene expression and T cell activation. Activated T cells produce the alpha subunit of the IL-2 receptor (CD25 or IL-2R), enabling a fully functional receptor that can bind with IL2, which in turn activates the T cell’s proliferation pathways
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