Year: 2026
Type: review
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.
Source: Frontiers in Immunology
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W7223001283