Functional association of Fc epsilon RI gamma with Arginine(632) of paired immunoglobulin-like receptor (PIR)-A3 in murine macrophages

Paired immunoglobulin-like receptors (PIR) are expressed on B cells and macrophages and include inhibitory and putative activating receptors referred to as PIR B and PIR-A, respectively. Although PIR-B's inhibitory pathway has been described, it is unknown whether PIR-A receptors can deliver activation signals to macrophages, and if so, through what mechanism. Here we use chimeric receptors to address the mechanisms of PIR-A signaling. Cotransfection of chimeric receptors comprised of the extracellular region of human CD4 and the transmembrane and cytoplasmic domains of murine PIR-A3 showed the ability of PIR-A3 to physically interact with the Fc epsilon Rl gamma chain in 293T cells. This interaction is dependent on Arg(632) within the PIR-A3 transmembrane domain. We also demonstrate PIR-A3 interaction with the endogenous Fc epsilon Rl gamma of the ANA-1 macrophage cell line, again in an Arg(632)-dependent manner. Furthermore, we show that crosslinking of these chimeric receptors synergizes with IFN-gamma in the production of nitric oxide. Our data are the first to show the potential of PIR-A3 to deliver activation signals to macrophages and establish its dependence on Arg632. These findings suggest that further study of the PIR-A receptors should be aggressively pursued toward a complete understanding of the intricate regulation of macrophage biology. This is a US government work. There are no restrictions on its use. [References: 37]

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