T cells are specialized white blood cells that serve as primary defenders within the body’s immune system, recognizing and eliminating threats such as viruses, bacteria, and cancerous cells. They are capable of orchestrating highly specific responses to diverse pathogens, making them central to adaptive immunity. Located on the surface of many immune cells, including T cells, is a protein known as CD38. The presence and varying levels of CD38 on T cells provide insights into their function and immune health.
Understanding CD38 on T Cells
CD38 is a transmembrane glycoprotein. This molecule acts both as an enzyme and a receptor. As an enzyme, CD38’s ADP-ribosyl cyclase activity converts nicotinamide adenine dinucleotide (NAD+) into cyclic ADP-ribose (cADPR). This enzymatic product, cADPR, is a secondary messenger that regulates intracellular calcium levels.
CD38 on T cells influences their behavior. Its enzymatic activity, leading to cADPR production, directly impacts calcium signaling within T cells. Calcium influx is fundamental for T cell activation and subsequent cellular responses, including gene expression and cytokine release. CD38 also functions as a receptor, participating in cell-to-cell interactions and adhesion. For instance, it can bind to CD31 on other cells, facilitating cellular communication and physical association between immune cells.
CD38 in Immune Regulation
CD38 expression levels on T cells indicate their activation status and functional state. When T cells encounter pathogens or foreign substances, they become activated, often leading to increased CD38 expression on their surface. Conversely, sustained high levels of CD38 can be associated with T cell exhaustion, a state where T cells lose their ability to effectively respond to antigens. This dual role highlights CD38’s complex involvement in immune responses.
The protein also influences T cell proliferation and differentiation into specialized subsets. CD38’s enzymatic activity, by consuming NAD+, impacts cellular metabolism, which is interconnected with T cell growth and division. This metabolic influence affects the development of different T helper cell subsets, such as Th1, Th2, or Th17 cells, each producing distinct sets of cytokines. CD38 can modulate the production of various cytokines, signaling molecules that regulate inflammation and immune suppression. For example, CD38 influences the production of pro-inflammatory cytokines like interferon-gamma (IFN-γ) or anti-inflammatory cytokines like interleukin-10 (IL-10), shaping the overall immune response.
CD38 as a Marker and Target in Disease
CD38 expression levels on T cells are valuable biomarkers across a range of diseases. In human immunodeficiency virus (HIV) infection, elevated CD38 on T cells, particularly CD8+ T cells, often correlates with disease progression and a poorer prognosis. This upregulation reflects chronic immune activation and inflammation characteristic of the disease. Similarly, in autoimmune conditions like rheumatoid arthritis and systemic lupus erythematosus, increased CD38 expression on T cells indicates disease activity and contributes to the pathogenic immune response.
Beyond its role as a marker, CD38 has emerged as a therapeutic target, particularly in oncology. Multiple myeloma, a cancer of plasma cells, frequently shows high levels of CD38 on malignant cells. This consistent expression makes CD38 an attractive target for therapeutic intervention. Monoclonal antibodies, such as daratumumab, have been developed to specifically bind to CD38 on cancer cells. These antibodies work by recruiting immune effector cells to destroy the CD38-expressing cancer cells through mechanisms like antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), or by inducing direct cell death.
Citations
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