The protein CD45 is on the surface of immune cells, where it participates in communication networks governing how these cells develop and respond to threats. CD45 is not a single entity; it exists in multiple forms, or isoforms, each with distinct structural characteristics. These different versions are foundational to understanding how immune cell functions are specialized and regulated.
The CD45 Protein Family: A General Overview
CD45, or Leukocyte Common Antigen (LCA), is a protein tyrosine phosphatase (PTP). Its job is to remove phosphate groups from other proteins, a biochemical switch that controls cellular signals. This function makes CD45 a regulator of signaling pathways activated by T-cell and B-cell antigen receptors, which recognize foreign invaders.
This protein is expressed on nearly all hematopoietic cells, including most immune cells and their precursors, but not mature red blood cells or platelets. By modulating intracellular signaling, CD45 influences immune cell development, maturation, and activation. The existence of various isoforms allows for refined control over these processes.
Generation of CD45 Isoforms: The Role of Alternative Splicing
The diversity of the CD45 protein family originates from a single gene, PTPRC, through a process called alternative splicing. This mechanism allows one gene to produce multiple proteins by selectively including or excluding gene segments called exons. During transcription into messenger RNA (mRNA), the cellular machinery can choose which exons to include.
For CD45, this variability is concentrated in the part of the gene coding for the protein’s extracellular domain. Specifically, three variable exons, A, B, and C (also numbered 4, 5, and 6), are subject to this splicing process. This results in CD45 proteins with extracellular domains of varying sizes and structures, which is the basis for their functional distinctions.
Major CD45 Isoforms and Their Expression Patterns
Alternative splicing gives rise to several major CD45 isoforms. One of the largest is CD45RABC, which includes all three variable exons. The most well-characterized isoforms are often defined by their reactivity with specific antibodies.
The isoform CD45RA includes exon A and is characteristic of naive T cells—those that have not yet encountered their specific antigen. It is also found on certain B cells and developing T cells in the thymus. In contrast, the CD45RO isoform is the smallest, as it lacks all three variable exons (A, B, and C), and is the hallmark of activated and memory T cells.
Another isoform, CD45RB, contains exon B, and its expression is high on naive T cells and B cell subsets but is downregulated as T cells become activated. The expression of these isoforms is dynamic, changing as an immune cell matures or transitions between functional states.
Functional Distinctions Among CD45 Isoforms
The structural differences in the extracellular domains of CD45 isoforms lead to distinct functional capabilities. The size of this external region influences how CD45 interacts with other molecules and regulates its enzymatic activity. Larger isoforms can create steric hindrance that impedes the interaction of other surface receptors, like the T-cell receptor (TCR).
Conversely, smaller isoforms like CD45RO permit closer contact between cells, which may facilitate more efficient signaling through the TCR complex during activation. The different isoforms also show varied abilities to form dimers or to associate with membrane microdomains known as lipid rafts.
Localization within or outside of these rafts can affect which substrate proteins the CD45 phosphatase can access, altering the signaling outcome. These molecular distinctions help set the activation threshold for T and B cells, determining how strong a signal is needed to trigger a response. The specific isoform expressed can also influence cell adhesion and the production of cytokines.
Clinical Relevance of CD45 Isoforms
The distinct expression patterns of CD45 isoforms are valuable in clinical diagnostics. Using a technique called flow cytometry, antibodies that recognize specific isoforms can identify and count different immune cell populations in blood samples. This allows clinicians to track the balance of naive and memory T cells, providing a snapshot of a person’s immune status or response to vaccination.
Alterations in these expression patterns are associated with some human diseases. In several autoimmune diseases, such as multiple sclerosis, a shift in the T-cell ratio often reflects chronic immune activation. Genetic variations in the PTPRC gene that affect splicing have been linked to susceptibility to both autoimmune conditions and certain infectious diseases.
In oncology, CD45 expression is a marker for identifying cancers of hematopoietic origin, like leukemias and lymphomas. Analyzing which isoforms are present can aid in classifying these malignancies and may serve as a prognostic indicator or therapeutic target.