The Cluster of Differentiation 71, or CD71, is a protein marker found on the surface of cells throughout the body and is also known as Transferrin Receptor 1 (TfR1). This protein is a type II transmembrane glycoprotein that exists as a disulfide-linked homodimer, meaning it is formed by two identical subunits. The main function of CD71 is to act as the gateway for iron to enter the cell, a process necessary for life functions. Because iron is required for fundamental cellular processes like DNA synthesis and energy production, the presence and regulation of this marker are tightly linked to cell activity and health, providing insights into normal physiology and disease states.
The Role of CD71 in Iron Transport
CD71 serves as the primary receptor for the iron-carrying protein transferrin, making it the gatekeeper for cellular iron acquisition. Free iron, which is toxic in high concentrations, is safely bound to transferrin in the bloodstream in its ferric state, or Fe(III). This iron-laden transferrin then circulates until it binds to the CD71 receptor expressed on the cell surface.
Once the complex of transferrin and iron is bound to CD71, the entire unit is internalized through a process called receptor-mediated endocytosis. This creates a small, membrane-bound compartment inside the cell called an endosome. Specialized ion pumps rapidly acidify the endosome, which causes the iron to dissociate from the transferrin protein.
The acidic environment triggers a change in the complex, allowing the iron to be reduced from Fe(III) to the more usable ferrous state, Fe(II), by an enzyme called STEAP3. This reduced iron is then exported out of the endosome and into the cell’s cytoplasm by the divalent metal transporter 1 (DMT1). After the iron is released, the CD71-transferrin complex is recycled back to the cell surface, where the neutral pH causes the now-iron-free transferrin to be released back into the circulation.
CD71 in Red Blood Cell Development
The process of forming red blood cells, known as erythropoiesis, requires iron for the synthesis of hemoglobin, the oxygen-carrying molecule. Consequently, developing red blood cells, or erythroid precursors, exhibit the highest expression of the CD71 marker found anywhere in the body. These precursor cells, such as proerythroblasts and erythroblasts in the bone marrow, are rapidly dividing and actively producing hemoglobin.
The expression of CD71 is precisely regulated as these cells mature, peaking during the stages of intense hemoglobin synthesis. As the cells advance toward becoming mature red blood cells, or erythrocytes, CD71 expression gradually decreases. The marker is lost entirely when the cells reach the final mature erythrocyte stage.
This tightly controlled expression pattern makes CD71 a useful clinical marker in hematology. Evaluating the number of CD71-positive cells in the bone marrow or peripheral blood provides a direct assessment of the rate of red blood cell production. For example, the presence of these immature, CD71-expressing cells in peripheral blood, which is normally absent in healthy adults, can indicate conditions like severe anemia, where the body is rapidly attempting to replenish its red blood cell supply. Monitoring CD71 levels helps clinicians evaluate iron status and diagnose various blood disorders.
Monitoring Cell Health and Disease
Beyond its normal function in iron transport and blood formation, CD71 is an indicator of cell proliferation. Since iron is necessary for cell division and DNA replication, any cell that is actively dividing, whether normally or abnormally, increases its expression of CD71 to meet its metabolic demands. This makes the marker a tool for monitoring cell health and diagnosing several diseases.
In cancer biology, the overexpression of CD71 is a common feature across many tumor types, including pancreatic, breast, and various hematologic malignancies. Cancer cells utilize this heightened expression to fuel their rapid, uncontrolled growth. This characteristic overexpression is being explored for therapeutic purposes, using the CD71 marker as a target to selectively deliver toxic agents to the malignant cells or to inhibit their iron uptake.
In laboratory diagnostics, CD71 is utilized in techniques like flow cytometry to identify and quantify proliferating cells in a sample. Its expression level often correlates with other markers of cell division, such as Ki-67, providing a direct measurement of how quickly a cell population is growing. This diagnostic utility extends to conditions like aggressive lymphomas, where high CD71 expression helps distinguish them from slower-growing, indolent forms. Furthermore, CD71 can be exploited by certain viruses, which use the receptor as a point of entry to infect cells, illustrating its broader biological significance in pathogen interaction.