CD38, or Cluster of Differentiation 38, is a protein located on the surface of many cells throughout the body. It is particularly abundant on immune cells, part of the body’s defense systems. This protein is not just a simple marker; it actively participates in a variety of cellular processes, and its involvement in immune responses, aging, and several diseases makes it a molecule of interest in health and medicine.
The Dual Roles of CD38
CD38 is a versatile molecule that performs two distinct jobs. It acts as both an enzyme and a receptor. These dual functions contribute to its influence over a wide range of biological activities, from energy regulation to cell-to-cell communication.
Its primary role is as an enzyme, acting as the main consumer of nicotinamide adenine dinucleotide (NAD+). NAD+ is a coenzyme present in all living cells and is used for processes like generating cellular energy and repairing damaged DNA. CD38 breaks down NAD+, and its enzymatic activity as an NADase is substantially higher than its other functions, meaning for every 100 NAD+ molecules it processes, the vast majority are simply consumed. This positions CD38 as a major regulator of NAD+ availability in the body’s tissues.
Simultaneously, CD38 functions as a receptor on the cell surface. It acts like a satellite dish, receiving signals from the cell’s surrounding environment. For instance, it can bind to a protein called CD31 on other cells, triggering a response inside the cell. This form of cellular communication allows cells to coordinate their actions, particularly within the immune system.
CD38 and the Immune System
Within the immune system, CD38 is found at high levels on a variety of cells, including T cells, B cells, natural killer (NK) cells, and macrophages. It actively participates in orchestrating an effective immune response. When immune cells are called into action to fight an infection or respond to tissue damage, CD38 expression is often increased, enhancing their capabilities.
One of its functions is helping immune cells migrate where needed. The enzymatic activity of CD38 helps trigger internal signals that lead to the expression of chemokine receptors, which guide cells toward sites of inflammation. This process, known as chemotaxis, ensures that immune cells can efficiently travel to and accumulate in areas of the body under attack by pathogens. Without this guidance, the immune response would be less effective.
CD38 ligation, or binding, can induce immune cells to become activated and proliferate. This is part of the signaling cascade that prepares a T cell or B cell for activation. Once activated, these cells release cytokines, which are signaling proteins that help coordinate the broader immune defense. CD38 modulates the release of these substances, ensuring a balanced and appropriate inflammatory response to threats like bacterial infections.
Connection Between CD38 and Aging
Research links CD38 and the natural aging process. As individuals get older, the expression and activity of CD38 increase substantially in many tissues. This age-related rise has consequences for cellular health, primarily through its enzymatic function of consuming NAD+.
The increased CD38 activity drives the decline in NAD+ levels that occurs with age. This is partly driven by an accumulation of senescent cells—older cells that have stopped dividing and secrete inflammatory signals. These signals promote the development of pro-inflammatory immune cells, such as M1-like macrophages, which have very high levels of CD38, creating a cycle that further depletes NAD+.
This reduction in NAD+ is directly linked to many aspects of aging. With less NAD+ available, the efficiency of mitochondria, the powerhouses of the cell, declines, leading to reduced cellular energy. The cell’s ability to repair DNA damage and carry out other maintenance functions is also impaired. This creates a feedback loop where low NAD+ can induce more cells to become senescent, which in turn drives more inflammation and higher CD38 activity, accelerating the aging process.
CD38 in Disease and Medicine
The functions of CD38 are also relevant in disease and medicine. Because its expression is very high on certain types of cancer cells, it has become a biomarker and therapeutic target. This is particularly true for blood cancers, such as multiple myeloma and some leukemias, where cancer cells have exceptionally high amounts of CD38 on their surface.
This high expression makes CD38 a target for cancer treatments. Scientists have developed monoclonal antibodies, such as daratumumab and isatuximab, that recognize and bind to CD38. Once these antibodies attach to CD38 on a cancer cell, they mark it for destruction by the immune system through a process called antibody-dependent cellular cytotoxicity. This approach allows for the targeted elimination of malignant cells while sparing many healthy ones.
Beyond cancer, the role of CD38 in regulating the immune system and inflammation is relevant in other medical areas. Researchers are exploring CD38 inhibitors for treating autoimmune conditions like systemic lupus erythematosus. Given its role in NAD+ metabolism, there is also growing interest in targeting CD38 to combat metabolic diseases and tissue fibrosis and potentially reverse associated cellular damage.