IMMUNE REGULATION BY IMMUNOGLOBULIN-LIKE RECEPTORS

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PIRs expressed on B and myeloid cells form a unique 'self' recognition. Activating PIR-A and inhibitory PIR-B were shown to bind various murine MHC class I (H-2) molecules. In vitro H-2 tetramer stimulation of PIRs induced intracellular phosphotyrosine signaling. PIR-B-deficient mice transferred with allogeneic splenocytes showed exacerbated graft-versus-host disease, which was due to the augmented activation of the recipient's dendritic cells (DCs) with the concomitant up-regulation of PIR-A and increased IFN-production. PIR-A-induced DC activation also led to increased proliferation of donor cytotoxic T cells. Thus, PIR-A and PIR-B are counter-acting receptors that play key roles for successful tissue transplantation, and may regulate irrelevant reaction to autologous tissues in a constitutive fashion under physiological circumstances.To analyze the etiology of mild osteopetrosis in DAP12 (DNAX protein 12)-deficient mice, we examined the bone morphology in FcRγ-deficient (FcRγ--) mice and DAP12/FcRγ double deficient (DKO) mice. Histological examination revealed that FcRγ--mice did not show any remarkable osteopetrosis. However, we found that DKO mice exhibited much more severe osteopetrosis than DAP12--mice, suggesting that either DAP12 or FcRγ is required for normal bone remodeling. In osteoclast precursor cells, FcRγ and DAP12 associate with multiple IgLRs including OSCAR and PIR-A ; and TREM-2 and SIRPβ1, respectively, and activate Ca^2 signal through PLCγ. Thus, ITAM-dependent costimulatory signals activated by multiple IgLRs are indispensable for the maintenance of bone homeostasis, indicating that RANK and M-CSF receptor are not sufficient to activate signals required for osteoclastogenesis.