The immune system relies on billions of cells communicating to determine when to launch an attack and when to stand down. Central to this communication network is CD45, a protein found on the surface of virtually all white blood cells. This molecule acts as a molecular switch that sets the sensitivity threshold for cell activation, controlling the body’s immune defenses against pathogens and disease.
What is CD45?
CD45 is a type I transmembrane protein, meaning it spans the entire cell membrane with a portion extending outside the cell and a large segment residing inside the cell. Found on all nucleated cells of the hematopoietic lineage, it is so prevalent that it was historically known as the Leukocyte Common Antigen (LCA). The official name for the gene that encodes it is PTPRC, reflecting its classification as a protein tyrosine phosphatase receptor type C.
The structure of CD45 is divided into three parts: an extracellular domain, a single transmembrane segment, and a large cytoplasmic tail. This intracellular segment is the functional part of the molecule, containing two tandem phosphatase domains. Only the first of these domains possesses the catalytic activity, which is the mechanism by which CD45 performs its regulatory function within the cell.
Regulating Immune Cell Signaling
The core function of CD45 is its enzymatic activity as a protein tyrosine phosphatase. Phosphatases remove phosphate groups from tyrosine amino acids on other proteins, reversing the action of protein tyrosine kinases. By controlling the addition and removal of these phosphate groups, CD45 acts as a switch that determines whether an immune cell will activate or remain inactive.
In T cells, this function is directed toward members of the Src family of kinases, specifically Lck and Fyn, which are essential for initiating the immune response. These kinases are normally kept in an inactive state by an inhibitory phosphate group attached to a specific C-terminal tyrosine residue. CD45 activates the T cell by removing this inhibitory phosphate group from Lck and Fyn.
Once the inhibitory phosphate is removed, Lck and Fyn become active, initiating the T cell receptor (TCR) signaling cascade. This rapid dephosphorylation by CD45 is necessary to lower the activation threshold, allowing the T cell to respond efficiently when it encounters a foreign antigen. Without functional CD45, Lck remains hyperphosphorylated and inactive, rendering the T cell unresponsive to stimulation and severely compromising the overall immune response.
The Different Forms of CD45
While the internal enzymatic domain of CD45 is identical across all immune cells, the external domain can vary. This variability gives rise to multiple forms, called isoforms, which are generated through a process known as alternative splicing of three specific exons in the gene. The expression of a particular CD45 isoform acts as a molecular marker that reflects the cell’s current state of maturity and activation.
Two of the most well-studied isoforms are CD45RA and CD45RO. CD45RA is a larger isoform expressed primarily on naive T cells, which are cells that have not yet encountered their specific antigen. This larger form is thought to slightly hinder T cell activation, maintaining the cell’s readiness at a higher threshold.
After a naive T cell activates, it sheds the larger exon segments and begins to express the shorter CD45RO isoform. This shorter form is characteristic of memory and activated T cells, which are poised to respond more quickly and vigorously to a second encounter with the same pathogen. The switch from the RA to the RO isoform provides a visual molecular signature of the cell’s history.
CD45 in Medical Testing
CD45 on white blood cells makes it a valuable tool in clinical diagnostics, particularly in the field of hematopathology. The primary technique used to leverage CD45 is flow cytometry, which uses fluorescent antibodies to identify and quantify different cell populations in blood or bone marrow. CD45 is used in a testing strategy called “gating” to quickly separate all leukocytes (white blood cells) from other, non-hematopoietic cells in a sample.
In the diagnosis of hematologic malignancies like leukemia and lymphoma, the expression level of CD45 is important. Normal mature white blood cells express high levels of CD45, but malignant blast cells often exhibit a characteristically low or “dim” expression. This difference in intensity, when plotted against the cell’s size (side scatter), allows clinicians to identify the abnormal blast population for diagnosis and to monitor the effectiveness of treatment. The use of specific antibodies to detect isoforms like CD45RA and CD45RO also enables doctors to track immune status in patients with immune deficiencies or autoimmune disorders.