The immune system relies on specialized white blood cells, T lymphocytes (T cells), which are the central architects of adaptive immunity. T cells recognize and remember specific foreign invaders. To execute their diverse roles, T cells exist in multiple states of maturity and activation, distinguished by proteins displayed on their surface. The markers CD44 and CD62L are routinely used to classify these cells, tracking their journey from an unexposed state to a highly reactive defender.
Molecular Roles of CD44 and CD62L
The CD62L protein, also known as L-selectin, is an adhesion molecule that functions primarily as a homing receptor. Its main role is to facilitate the entry of T cells from the bloodstream into secondary lymphoid organs, such as lymph nodes. CD62L binds to specific carbohydrate structures, called addressins, on the lining of blood vessels. This binding initiates a process that allows the T cell to migrate out of circulation into the lymph node tissue.
The presence of CD62L indicates a T cell is actively circulating and capable of immune surveillance within lymphoid structures. Upon full activation by an antigen, the CD62L molecule is rapidly cleaved, or “shed,” from the cell surface. This shedding prevents the activated T cell from re-entering the lymph node, freeing it to patrol peripheral tissues where infection is located.
In contrast, the CD44 glycoprotein is a versatile adhesion molecule that binds to components of the extracellular matrix, notably hyaluronic acid. CD44 expression is low on resting, unactivated T cells. Following activation, CD44 expression is dramatically upregulated and remains high on antigen-experienced cells.
This high expression level helps activated T cells adhere to and migrate through tissues, especially in inflamed areas where hyaluronic acid is abundant. CD44 is also involved in transmitting signals that influence T cell survival and movement within non-lymphoid tissues. The combination of CD44’s activation-linked expression and CD62L’s traffic-regulating function defines T cell populations.
Classification of T Cell Subsets
The dual expression pattern of CD44 and CD62L classifies T cells into three primary, functionally distinct subsets.
Naive T Cells (TN)
Naive T cells (TN) have never encountered their specific antigen and are characterized by a CD44 low/CD62L high phenotype. These cells are constantly circulating, using their high CD62L expression to enter lymph nodes and screen for foreign material presented by antigen-presenting cells. They are metabolically quiet and have a long lifespan, awaiting the signal that triggers activation.
Central Memory T Cells (TCM)
After initial antigen encounter, Naive T cells differentiate into memory populations distinguished by high CD44 expression. Central Memory T cells (TCM) retain the CD62L high marker, resulting in a CD44 high/CD62L high phenotype. The preserved CD62L expression enables TCM cells to home efficiently back into secondary lymphoid organs. This localization allows them to quickly encounter antigen-presenting cells upon re-infection, where they rapidly proliferate and initiate a robust immune response.
Effector Memory T Cells (TEM)
The third major population is the Effector Memory T cell (TEM) subset, defined by a CD44 high/CD62L low profile. The absence of CD62L excludes these cells from re-entering most lymph nodes. Instead, they favor circulation in the peripheral blood and migration into non-lymphoid tissues, such as the lungs, liver, and skin. This tissue tropism positions them to act immediately upon re-encountering a pathogen. A highly differentiated subset, TEMRA cells, shares the CD62L low status of TEM cells but re-expresses the CD45RA marker.
Immune Functions of T Cell Subsets
The phenotypic classification based on CD44 and CD62L directly correlates with the functional roles of each T cell subset.
Naive T cells are the immune system’s reserve force, maintaining quiescence and surviving for years without division. Their activation requires a complex, strong signal, leading to a relatively slow initial response necessary to generate new specificity against previously unseen threats. Upon successful activation, these cells are the source material for all subsequent effector and memory populations.
Central Memory T cells represent a highly mobile recall population, functioning through their ability to circulate through lymphoid organs. Since they are antigen-experienced, they have a lower activation threshold than Naive cells. Their high CD62L status positions them within the lymph nodes to rapidly proliferate into large numbers of effector cells upon secondary infection. This capacity for expansion makes TCM cells the orchestrators of sustained, long-term protection.
Effector Memory T cells are the immune system’s first responders, focusing on immediate action rather than sustained proliferation in lymphoid tissues. Their CD62L low status dictates their patrol of peripheral, non-lymphoid sites. This allows them to rapidly deploy effector functions, such as cytotoxicity or cytokine release, directly at the site of pathogen entry. This rapid, on-site response is crucial for quickly limiting pathogen spread during a secondary infection.
Relevance in Disease and Therapy
Monitoring the balance between these T cell subsets provides valuable insight into the state of a patient’s immune health, especially in contexts like chronic infection and aging.
Chronic Infection and Aging
Persistent viral infection or immunosenescence (immune aging) is characterized by a noticeable shift in the CD44/CD62L balance. The proportion of Naive T cells (CD44 low/CD62L high) decreases, while highly differentiated Effector Memory (CD44 high/CD62L low) and TEMRA cells increase. This shift signals a depletion of the immune system’s capacity to respond to new pathogens and indicates chronic immune activation.
Cancer Immunotherapy (CAR T Cells)
In cancer immunotherapy, particularly CAR T cell therapy, the CD44/CD62L profile of engineered cells is a factor for treatment success. Researchers have found that CAR T cell products enriched with less-differentiated, CD62L high Naive and Central Memory T cells often lead to superior and more persistent anti-tumor responses in patients. These cells can home more effectively to tumor-draining lymph nodes, proliferate extensively, and survive longer in vivo, providing durable cancer surveillance.
Manufacturing and Vaccine Efficacy
The expression of CD62L is also leveraged to improve the manufacturing of therapeutic cells. New targeted lentiviral vectors preferentially transduce CD62L-expressing T cells. This method streamlines production by selecting cells with potential for long-term function and persistence. Vaccine efficacy is often assessed by measuring the generation of robust Central and Effector Memory populations, using CD44/CD62L markers to confirm successful long-term immunological memory.