T cells are central players in the adaptive immune system, identifying and eliminating specific threats like viruses and bacteria. These cells circulate throughout the body, acting as specialized sentinels that must be tightly regulated to prevent them from attacking healthy tissue. T cells possess various surface proteins, or markers, which dictate their functional status and maturity. One such marker is the CD27 receptor, which significantly controls the T cell’s overall fate and function. Understanding CD27 expression patterns is a powerful way to track the history and capabilities of different T cell populations during an immune response.
CD27 as a Co-Stimulatory Signal
T cell activation requires two distinct signals to ensure the immune response is targeted and appropriate. The first signal is specific, delivered when the T cell receptor recognizes an antigen fragment presented by an antigen-presenting cell. The second signal, known as co-stimulation, is non-specific and acts as a confirmation switch to initiate a full-scale response. CD27 serves as a component of this second signal, ensuring the T cell is properly engaged.
This receptor belongs to the Tumor Necrosis Factor Receptor Superfamily (TNFRSF), which regulates cell survival and death. The specific binding partner, or ligand, for CD27 is CD70, primarily found on activated immune cells like dendritic cells, B cells, and T cells. The interaction between CD27 on the T cell and CD70 on the presenting cell boosts T cell proliferation and survival.
The resulting signal promotes the clonal expansion of T cells that have recognized an antigen, allowing them to rapidly multiply into effector cells. This mechanism also provides protective signals that counter programmed cell death (apoptosis), allowing activated T cells to survive long enough to clear the infection. By enhancing cell survival and promoting differentiation, the CD27-CD70 axis shapes the magnitude and duration of the T cell response.
Defining T Cell Subsets and Immune Memory
The presence or absence of CD27 acts as a molecular timeline, providing a roadmap for T cell maturation and classification. Most Naïve T cells, which have not yet encountered their specific antigen, constitutively express high levels of CD27. This suggests these cells are primed to receive the co-stimulatory signal when they first meet their target.
Following activation, T cells evolve into different memory subsets, and CD27 expression helps distinguish these populations. Central Memory T cells (TCMs) typically remain CD27-positive and provide long-term protection, quickly migrating to lymph nodes upon re-exposure to an antigen. The sustained expression of CD27 in this population contributes to their enhanced survival capacity.
In contrast, T cells often lose CD27 expression as they become more specialized and terminally differentiated. Effector Memory T cells (TEMs) can be CD27-positive or CD27-negative; the CD27-negative subset represents a more differentiated cell rapidly deployable to peripheral tissues. Terminally Differentiated Effector T cells, sometimes called T-effector memory cells re-expressing CD45RA (TEMRAs), are frequently CD27-negative.
The loss of CD27 marks a shift toward a specialized, short-lived effector phenotype with immediate killing capabilities. These CD27-negative cells are highly differentiated and show a strong, immediate antigen-recall response, often secreting a broad range of effector cytokines. Monitoring the transition from CD27-positive to CD27-negative helps track a T cell’s “age” and its journey from an inexperienced Naïve cell to an experienced Effector cell.
Therapeutic and Diagnostic Importance
The predictable changes in CD27 expression make it a valuable tool in clinical settings for both diagnosis and therapeutic targeting. In chronic infections, such as HIV or tuberculosis, tracking CD27 expression serves as a biomarker for chronic immune activation and exhaustion. The persistent presence of antigen drives T cells to a highly differentiated state, leading to a noticeable increase in CD27-negative T cells in the blood.
A decrease in CD27 on T cells is associated with a reduced capacity for long-term survival and proliferation, which can predict the progression of immune dysfunction. Clinicians use flow cytometry to measure the ratio of CD27-positive to CD27-negative cells, gauging the severity of the infection and the degree of immune system wear-and-tear. This diagnostic insight helps monitor disease activity and the effectiveness of antiviral or antimicrobial therapies.
The CD27-CD70 pathway has become a promising target in cancer immunotherapy. Monoclonal antibodies that act as agonists (meaning they stimulate the receptor) are being developed to enhance the anti-tumor response. By activating CD27 on T cells within the tumor microenvironment, these antibodies provide a potent co-stimulatory signal that promotes T cell proliferation, survival, and cytotoxic function.
This therapeutic strategy is relevant in Chimeric Antigen Receptor (CAR) T cell therapy. Incorporating the CD27 signaling domain into the CAR construct improves the persistence and anti-tumor activity of the transferred T cells. By enhancing T cell survival, CD27 signaling helps ensure therapeutic cells remain active long enough to achieve sustained tumor clearance.