CD271: Roles in Immunology, Neural Crest Cells, and Beyond

CD271, also known as the low-affinity nerve growth factor receptor (LNGFR), plays a crucial role in cellular processes. While primarily recognized for its involvement in neural crest-derived cells and immune function, research continues to reveal its broader significance in tissue regeneration, cancer biology, and stem cell regulation. Understanding its diverse functions sheds light on both normal physiology and disease mechanisms.

Given its presence across multiple tissues and interactions with numerous signaling pathways, CD271 influences key aspects of cell survival, differentiation, and immune responses.

Receptor Structure And Associated Ligands

CD271 is a transmembrane glycoprotein in the tumor necrosis factor receptor (TNFR) superfamily. Its structure includes an extracellular domain with four cysteine-rich repeats, a single-pass transmembrane region, and an intracellular domain that lacks enzymatic activity. Unlike receptor tyrosine kinases, which signal through phosphorylation, CD271 relies on adaptor proteins to mediate downstream effects, making it a versatile signaling hub.

The extracellular domain binds neurotrophins such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4). NGF, the most studied, plays a key role in neuronal survival and apoptosis. Unlike high-affinity tropomyosin receptor kinase (Trk) receptors, which drive cell survival, CD271 can induce both survival and apoptosis depending on cellular context and co-receptor availability.

CD271 also interacts with pro-neurotrophins in complex with sortilin, a Vps10p-domain sorting receptor, triggering apoptotic pathways, particularly during neuronal pruning or injury. Additionally, it binds extracellular matrix components such as laminin and fibronectin, suggesting roles in cell adhesion and migration. These interactions extend its function beyond neurotrophic signaling to tissue remodeling and cellular plasticity.

Distribution In Human Tissues

CD271 is expressed across various human tissues, reflecting its diverse regulatory functions. In the central and peripheral nervous systems, it is found in neural progenitor cells, Schwann cells, and oligodendrocyte precursor cells, contributing to neurogenesis, myelination, and axonal regeneration. Its presence in sensory and autonomic ganglia supports neuronal survival and neurotrophic signaling, particularly during development and injury response.

Outside the nervous system, CD271 marks mesenchymal stem cells (MSCs) from bone marrow, adipose tissue, and dental pulp. It identifies a subset of MSCs with enhanced differentiation potential, particularly toward osteogenic and chondrogenic lineages, suggesting a role in bone remodeling and cartilage repair. Its expression in perivascular cells indicates involvement in vascular stability and tissue regeneration, highlighting its significance in wound healing.

In epithelial tissues, CD271 is found in basal cell populations of the skin and mucosal linings. In the epidermis, it is expressed in keratinocyte progenitors, where it influences cell adhesion and stratification. In the gastrointestinal tract, CD271-positive cells in intestinal crypts suggest a role in epithelial renewal. This distribution aligns with its interactions with extracellular matrix components, reinforcing its role in tissue integrity and migration.

Involvement In Neural Crest-Derived Cells

CD271 plays a key role in neural crest-derived cells, a migratory and multipotent population that forms diverse tissues during embryonic development. It is highly expressed in neural crest progenitors, influencing cell fate, migration, and survival. During early development, CD271 regulates the balance between proliferation and differentiation, determining whether cells become neuronal, glial, or mesenchymal.

As neural crest cells migrate and differentiate, CD271 continues to shape lineage specification, particularly in peripheral nervous system formation. Schwann cell precursors, which originate from neural crest cells, express CD271 during early development. This receptor facilitates their transition into mature Schwann cells responsible for myelination and nerve repair. CD271-positive Schwann cell precursors retain plasticity, allowing them to contribute to both myelinating and non-myelinating populations depending on environmental cues. This adaptability is crucial in nerve regeneration, where CD271 expression is upregulated to promote repair.

Beyond the nervous system, CD271 influences neural crest-derived mesenchymal cells, including those forming craniofacial structures, smooth muscle, and adipose tissue. In cranial neural crest populations, it regulates chondrogenic and osteogenic differentiation, contributing to skull and jaw formation. Its expression in dental pulp-derived stem cells underscores its role in odontogenesis, where it drives the development of dentin-producing odontoblasts. Similarly, in vascular smooth muscle progenitors, CD271 helps maintain contractile and synthetic phenotypes, essential for blood vessel integrity.

Role In Immunological Responses

CD271 regulates immune activity, influencing both innate and adaptive responses. It is expressed in subsets of macrophages, dendritic cells, and T lymphocytes, shaping inflammation, antigen presentation, and cellular activation. Unlike classical immune receptors that directly mediate immune signaling, CD271 acts as a modulator, adjusting immune cell behavior by altering survival thresholds and inflammatory signaling.

In macrophages, CD271 expression is linked to an anti-inflammatory phenotype. CD271-positive macrophages produce lower levels of pro-inflammatory cytokines such as TNF-α and IL-6 while promoting tissue repair through increased IL-10 secretion.

In dendritic cells, CD271 influences maturation and T cell interactions. Research suggests that CD271 expression can suppress dendritic cell activation, impairing T cell priming and promoting immune tolerance. This mechanism is relevant in tumor immunology, where CD271-expressing dendritic cells contribute to immune evasion by dampening antitumor T cell responses. Conversely, in autoimmunity, reduced CD271 expression is associated with heightened immune activation, suggesting a protective role against excessive inflammation.

Links To Cellular Differentiation

CD271 modulates the balance between stemness and lineage commitment across multiple tissues. Its expression is often linked to progenitor cell populations, where it serves as a regulatory switch for differentiation. In neural progenitors, CD271 influences the transition from undifferentiated stem cells to mature neurons and glial cells, mediated by neurotrophin interactions that either promote survival or induce apoptosis depending on co-receptor availability. This ensures proper neuronal patterning during development.

Beyond the nervous system, CD271 is a key marker for mesenchymal stem cells (MSCs), influencing osteogenic, chondrogenic, and adipogenic differentiation. CD271-positive MSCs exhibit greater osteogenic potential than their CD271-negative counterparts, highlighting its role in bone formation and repair. It is also expressed in periosteal progenitor cells, which contribute to bone remodeling after injury. In adipogenic differentiation, CD271 expression declines as progenitor cells commit to mature adipocytes, suggesting its role in maintaining progenitor identity. These findings underscore CD271’s importance in tissue regeneration and repair, where it acts as a gatekeeper of lineage commitment.

Interactions With Other Receptors

CD271 integrates signals from multiple receptor systems to regulate cellular outcomes. One of its most studied interactions is with the tropomyosin receptor kinase (Trk) family, particularly TrkA, TrkB, and TrkC. While Trk receptors mediate pro-survival signaling in response to neurotrophins, CD271 can modify these responses by either enhancing or inhibiting downstream pathways. In neural cells, CD271-TrkA complexes promote neuronal differentiation, whereas CD271 alone can induce apoptosis in the absence of Trk signaling.

CD271 also interacts with sortilin, a Vps10p-domain receptor that binds pro-neurotrophins. The CD271-sortilin complex triggers apoptotic pathways, particularly during neuronal pruning. This interaction is essential for sculpting neural circuits, ensuring only functionally integrated neurons survive.

Outside the nervous system, CD271 interacts with integrins, which regulate adhesion and migration. These interactions are particularly relevant in mesenchymal stem cells, where CD271-integrin signaling contributes to cell motility and tissue remodeling.