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Peer-reviewedCC BY 4.0Frontiers in Immunology

Beyond the classical Fc receptor: CD64 in phagocytosis and trained immunity

  • Zhaoxia Qu1,2,3
  • Hongqiao Zhang1,2
  • Steven D. Shapiro1,2,3,4
  • Gutian Xiao1,2,3
4 affiliations
  1. 1Department of Immunology and Immune Therapeutics, Keck School of Medicine, University of Southern California
  2. 2Hastings Center for Pulmonary Research, Keck School of Medicine, University of Southern California
  3. 3USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California
  4. 4Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Keck School of Medicine, University of Southern California
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Abstract

CD64 (FcγRI) is traditionally categorized as the high-affinity receptor for immunoglobulin G (IgG) and as a downstream effector of adaptive humoral responses for myeloid-driven clearance and immune programs. Accumulating evidence in myeloid cell biology, however, highlights a major historical oversight: CD64 also operates as a multimodal innate immunoreceptor capable of antibody-independent pattern recognition receptor (PRR) behavior. Synthesizing over three decades of data, this review spotlights the direct interaction of CD64 with humoral pentraxins and microbial outer membrane structures independent of IgG opsonization. We consolidate the biological mechanisms by which CD64 functions as an opsonin receptor or a direct PRR to drive phagocytosis and immune signaling pathways. Because trained immunity is antibody-independent, we introduce an unaddressed paradigm for how CD64 utilizes its non-classical, primordial PRR identity to guide myeloid cells to establish and maintain innate immune memory. This framework resolves a profound evolutionary and teleological conundrum: why frontline myeloid lineages constitutively express and exponentially upregulate CD64 days before pathogen-specific antibodies are manufactured, leveraging an ancient, non-specific pattern-sensing scaffold. Finally, we conceptualize the multi-tiered regulation of CD64 as a precise, localized translational target and predictive biomarker to safely bypass the potential risks of global metabolic and epigenetic therapies.

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Cite

BibTeXRIS
BibTeX
@article{qu2026beyond,
  title = {{Beyond the classical Fc receptor: CD64 in phagocytosis and trained immunity}},
  author = {Zhaoxia Qu and Hongqiao Zhang and Steven D. Shapiro and Gutian Xiao},
  journal = {Frontiers in Immunology},
  year = {2026},
  month = oct,
  doi = {10.3389/fimmu.2026.1985821},
  url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1985821/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Beyond the classical Fc receptor: CD64 in phagocytosis and trained immunity
AU  - Zhaoxia Qu
AU  - Hongqiao Zhang
AU  - Steven D. Shapiro
AU  - Gutian Xiao
PY  - 2026
DA  - 2026/10/20
JO  - Frontiers in Immunology
DO  - 10.3389/fimmu.2026.1985821
UR  - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1985821/full
AB  - CD64 (FcγRI) is traditionally categorized as the high-affinity receptor for immunoglobulin G (IgG) and as a downstream effector of adaptive humoral responses for myeloid-driven clearance and immune programs. Accumulating evidence in myeloid cell biology, however, highlights a major historical oversight: CD64 also operates as a multimodal innate immunoreceptor capable of antibody-independent pattern recognition receptor (PRR) behavior. Synthesizing over three decades of data, this review spotlights the direct interaction of CD64 with humoral pentraxins and microbial outer membrane structures independent of IgG opsonization. We consolidate the biological mechanisms by which CD64 functions as an opsonin receptor or a direct PRR to drive phagocytosis and immune signaling pathways. Because trained immunity is antibody-independent, we introduce an unaddressed paradigm for how CD64 utilizes its non-classical, primordial PRR identity to guide myeloid cells to establish and maintain innate immune memory. This framework resolves a profound evolutionary and teleological conundrum: why frontline myeloid lineages constitutively express and exponentially upregulate CD64 days before pathogen-specific antibodies are manufactured, leveraging an ancient, non-specific pattern-sensing scaffold. Finally, we conceptualize the multi-tiered regulation of CD64 as a precise, localized translational target and predictive biomarker to safely bypass the potential risks of global metabolic and epigenetic therapies.
SN  - 1664-3224
ER  -