CD300C

CD300C is an activating immunoreceptor of the immunoglobulin superfamily that functions as a paired counterpart to the inhibitory receptor CD300A, recognizing the shared lipid ligands phosphatidylethanolamine and phosphatidylserine on apoptotic cells but transducing activating signals through obligate association with the FcR-γ adaptor chain (PMID:23372157, PMID:29906528). Expressed on monocytes, basophils, mast cells, and cytokine-stimulated CD56bright NK cells, CD300C cross-linking triggers calcium mobilization, MAPK and NF-κB signaling, degranulation, inflammatory cytokine production, and monocyte-to-M1 macrophage differentiation (PMID:23571507, PMID:27040328, PMID:38159528). CD300C also functions as a T cell co-inhibitory molecule when presented as a soluble Fc-fusion protein, suppressing T cell proliferation and cytokine secretion and attenuating graft-versus-host disease and collagen-induced arthritis in mouse models, though its T cell counter-receptor remains unidentified (PMID:30498497, PMID:34021311). Antibody-mediated CD300C engagement on monocytes promotes macrophage differentiation that reduces amyloid-β plaque burden in a mouse model of Alzheimer's disease (PMID:40426995).

1. 1998 Medium

   Initial molecular cloning established CD300C (CMRF-35-H9) as a type I transmembrane glycoprotein with a single IgV-like ectodomain and cytoplasmic regulatory motifs, placing it among leukocyte receptors with potential signaling roles.

   Evidence Expression cloning and cDNA structural analysis

   PMID:9701027

   Open questions at the time

   • No functional signaling data provided
   • Cell-type expression pattern not systematically defined
   • No ligand identified
2. 2013 High

   Two studies established that CD300C is an FcR-γ-dependent activating receptor on monocytes and mast cells, identified phosphatidylethanolamine and apoptotic cells as ligands, and showed that co-expression of the inhibitory receptor CD300A dampens CD300C-mediated signaling, revealing a paired receptor system.

   Evidence Reporter cell lines with chimeric receptors, antibody cross-linking, calcium mobilization, cytokine assays, co-expression experiments on primary monocytes

   PMID:23372157 PMID:23571507

   Open questions at the time

   • Structural basis for differential PE binding between CD300A and CD300C not resolved at atomic level
   • Signaling intermediates downstream of FcR-γ not fully mapped
   • In vivo significance of paired receptor balance not tested
3. 2016 High

   CD300C was shown to be selectively induced on CD56bright NK cells by IL-2/IL-15 via STAT5 signaling, extending its functional relevance beyond myeloid cells and demonstrating that it enhances NK cell degranulation and cytokine secretion.

   Evidence Flow cytometry, STAT5 inhibition, cytokine neutralization, degranulation assays on primary NK cell subsets

   PMID:27040328

   Open questions at the time

   • Whether CD300C ligands on target cells directly trigger NK killing not tested
   • Functional interplay with CD300A on NK cells in vivo not addressed
4. 2018 High

   CD300C was identified as a costimulatory activating receptor on basophils that amplifies FcεRI-mediated responses, and separately as a T cell co-inhibitory molecule whose soluble form suppresses T cell activation and attenuates GVHD in vivo, revealing a dual role depending on cellular context.

   Evidence Basophil phosphorylation/degranulation assays with primary cells; soluble CD300c-Fc fusion protein T cell proliferation assays and in vivo GVHD mouse model

   PMID:29906528 PMID:30498497

   Open questions at the time

   • T cell counter-receptor for CD300C not identified
   • Whether the T cell inhibitory function operates in cis or trans on antigen-presenting cells not resolved
   • Relative contribution of PS versus PE binding to basophil costimulation unclear
5. 2022 Medium

   The T cell co-inhibitory function of CD300C was validated in a second autoimmune model, showing that CD300c-Ig fusion attenuates collagen-induced arthritis by suppressing Th1/Th17 responses and autoantibody production.

   Evidence CIA mouse model with prevention and treatment arms, cytokine ELISA, T cell proliferation, flow cytometry

   PMID:34021311

   Open questions at the time

   • Counter-receptor identity still unknown
   • Mechanism of action on antigen-specific T cells (direct vs indirect) not delineated
   • All in vivo data from single laboratory
6. 2023 Medium

   The downstream signaling mechanism of CD300C in monocyte-to-macrophage differentiation was defined as MAPK- and NF-κB-dependent, and antibody-mediated CD300C engagement drove M1 polarization with PD-L1 upregulation and antitumor activity in vivo.

   Evidence Monoclonal antibody CL7, pathway inhibition in THP-1 cells, CT26 tumor mouse model

   PMID:38159528

   Open questions at the time

   • Whether antitumor effect is macrophage-autonomous or requires adaptive immunity not resolved
   • Direct NF-κB/MAPK activation versus indirect effects not fully dissected
   • Relevance to human tumors not established
7. 2025 Medium

   Antibody-mediated CD300C engagement was shown to promote macrophage differentiation that clears amyloid-β plaques and improves cognition in a 5xFAD Alzheimer's disease mouse model, extending the receptor's therapeutic relevance to neurodegeneration.

   Evidence CB201 antibody, surface plasmon resonance, in vitro macrophage differentiation, 5xFAD mouse behavioral and histological analysis

   PMID:40426995

   Open questions at the time

   • Mechanism by which CD300C-differentiated macrophages clear Aβ not defined
   • Single mouse model, single lab
   • Human CNS relevance of peripheral monocyte-derived macrophage effects unconfirmed

• The identity of the T cell counter-receptor for CD300C remains unknown, and the structural basis for how the same IgV domain mediates activating signaling on myeloid/NK cells while delivering co-inhibitory signals to T cells has not been resolved.
• Counter-receptor identification needed
• No crystal structure of CD300C ectodomain or CD300C–lipid complex
• In vivo relevance of paired CD300A/CD300C balance in human disease not directly demonstrated