CD45RA is a protein marker found on the surface of specific immune cells. It acts as a molecular regulator that helps control the initiation of immune responses. CD45RA is one of several forms, or isoforms, of the larger CD45 protein, which is present on all white blood cells. The presence or absence of CD45RA indicates a cell’s history and its readiness to respond.
What Exactly is CD45RA?
CD45 is a large protein encoded by a single gene called PTPRC (Protein Tyrosine Phosphatase Receptor Type C). The gene produces multiple distinct versions of the protein through a process known as alternative splicing, where different sections of the gene’s instructions are included or excluded. CD45RA is the specific isoform that includes a particular section of the genetic code, known as exon A.
This inclusion of exon A gives the CD45RA molecule a large and bulky extracellular domain, the part of the protein that sticks out from the cell surface. The other major isoform, CD45RO, lacks this exon and possesses a much shorter extracellular domain. All CD45 isoforms, including CD45RA, share the same internal structure, which features two phosphatase domains.
This shared internal region gives CD45 its primary function as a receptor tyrosine phosphatase, an enzyme that removes phosphate groups from other proteins inside the cell. The difference between the isoforms lies in how their unique external domains influence this internal enzymatic activity. The large external structure of CD45RA affects its ability to interact with other cell surface receptors, subtly changing the cell’s signaling dynamics compared to the shorter CD45RO isoform.
Distinguishing Naive Immune Cells
The primary use of CD45RA is as a definitive surface marker to identify naive T cells, which are immune cells that have not yet encountered their specific target antigen. Naive T cells are characterized by being \(\text{CD45RA}^+\) and circulate throughout the body, waiting for the signal to begin an immune response. Once a naive T cell is activated by an antigen, it immediately stops producing the CD45RA isoform and begins producing the shorter \(\text{CD45RO}\) isoform instead.
This switch from \(\text{CD45RA}^+\) to \(\text{CD45RO}^+\) is a permanent marker of a cell’s activation and differentiation into a memory or effector cell. Memory T cells are the immune system’s long-term defense force, maintaining readiness to respond rapidly to a previously encountered threat. The presence of the \(\text{CD45RO}\) isoform indicates the cell has a history of activation.
The \(\text{CD45RA}\) marker is also used in conjunction with other molecules, such as CCR7, to refine T cell subsets. For instance, \(\text{CD45RA}^+\) cells that also express CCR7 are considered true naive T cells. A small subset of highly differentiated memory cells, known as \(\text{T}_{\text{EMRA}}\) (Effector Memory T cells re-expressing \(\text{CD45RA}\)), also re-express the \(\text{CD45RA}\) marker. These \(\text{T}_{\text{EMRA}}\) cells are distinct because they lack CCR7 and possess characteristics of aged, terminally differentiated cells.
How CD45RA Regulates Immune Responses
CD45RA functions as a regulator of T cell activation by controlling the activity of key signaling proteins inside the cell. The internal phosphatase domains of CD45 remove phosphate groups from signaling molecules, such as the Src family kinases Lck and Fyn. By dephosphorylating an inhibitory site on Lck, CD45 helps keep the T cell receptor (TCR) signaling machinery in a ready state.
The large size of the \(\text{CD45RA}\) extracellular domain influences the physical interaction between \(\text{CD45}\) and the \(\text{TCR}\) complex at the cell surface. When a T cell encounters an antigen-presenting cell, the TCR forms a tight cluster called the immunological synapse. The bulky \(\text{CD45RA}\) molecule is physically excluded from this tight cluster more easily than the shorter \(\text{CD45RO}\) isoform.
This exclusion of \(\text{CD45RA}\) from the synapse prevents the phosphatase from deactivating the newly activated \(\text{TCR}\) signaling molecules. Therefore, the \(\text{CD45RA}\) isoform on naive T cells is associated with a higher activation threshold, meaning the cell requires a stronger and more sustained antigen signal to become fully activated. In contrast, the shorter \(\text{CD45RO}\) isoform on memory cells is less easily excluded, contributing to the memory cell’s lower activation threshold and its ability to respond quickly to a re-infection.
Tracking Immune Health and Disease
Measuring the proportion of \(\text{CD45RA}^+\) cells in the blood is a standard practice in clinical immunology, typically performed using flow cytometry. This measurement provides valuable insight into the overall health and maturity of a person’s immune system. A high percentage of \(\text{CD45RA}^+\) naive T cells indicates a robust, youthful immune system with a broad capacity to respond to new pathogens.
Conversely, a decrease in the ratio of \(\text{CD45RA}^+\) (naive) to \(\text{CD45RO}^+\) (memory) cells is a hallmark of immunosenescence, or the aging of the immune system. This shift reflects a loss of new T cell production and an accumulation of long-lived memory cells. This is associated with increased susceptibility to infections and reduced vaccine efficacy in older adults. The re-expression of \(\text{CD45RA}\) on \(\text{T}_{\text{EMRA}}\) cells is also monitored, as their accumulation is a sign of immune aging and chronic inflammation.
\(\text{CD45RA}\) tracking is also used to monitor immune reconstitution after hematopoietic stem cell transplantation (HSCT). Selective depletion of \(\text{CD45RA}^+\) cells from a donor’s graft before transplantation is a strategy used to prevent graft-versus-host disease (GvHD). Naive T cells are the primary mediators of this reaction. By removing the \(\text{CD45RA}^+\) population, clinicians can safely infuse the memory \(\text{CD45RA}^-\) cells, which accelerate the patient’s recovery of immune function with a lower risk of complications.