The CD3 gene serves as a foundational element within the immune system, particularly for T cells. This gene encodes proteins that are necessary for T cells to function properly. Without these proteins, T cells, which are specialized white blood cells, would not be able to carry out their roles in protecting the body.
The CD3 Proteins and Their Role
The CD3 gene encodes proteins that form the CD3 complex. This complex is found on the surface of T cells. The CD3 complex is made up of several protein chains, specifically CD3γ, CD3δ, two CD3ε chains, and a CD3ζ chain (CD247).
These individual CD3 chains associate non-covalently with the T-cell receptor (TCR) to form the TCR-CD3 complex. The TCR itself is responsible for recognizing specific foreign invaders or abnormal cells by binding to antigens presented on other cells. However, the TCR has a short internal tail, preventing it from sending signals into the cell on its own.
The CD3 chains contain internal segments known as immunoreceptor tyrosine-based activation motifs (ITAMs). When the TCR binds to an antigen, it causes a change in the CD3 complex, leading to the phosphorylation of these ITAMs. This phosphorylation acts like a switch, initiating the transmission of signals from the cell surface into the T cell’s interior, which is necessary for T-cell activation.
CD3 in Orchestrating Immune Responses
The signaling initiated by the CD3 complex leads to a cascade of events for immune responses. Once the ITAMs on the CD3 chains are phosphorylated, they recruit an enzyme called Zap70, which activates. This activation of Zap70 further phosphorylates other targets within the cell, including a scaffold protein called LAT and an adapter molecule called SLP-76, initiating a series of intracellular signaling pathways.
These pathways lead to the production of second messengers, such as calcium ions, diacylglycerol (DAG), and inositol triphosphate (IP3). These messengers activate transcription factors like NF-κB, AP-1, and NFAT. This activates gene transcription, resulting in the proliferation of T cells, their differentiation into specialized effector cells, and the production of signaling molecules called cytokines.
Effector T cells include helper T cells, which coordinate immune responses, and cytotoxic T lymphocytes, which directly kill infected or cancerous cells. Through these coordinated actions, activated T cells, driven by CD3-mediated signaling, combat infections, eliminate cancerous cells, and regulate immune reactions. The number of ITAMs within the TCR-CD3 complex is also linked to distinct T-cell functions, with higher numbers for T-cell proliferation and lower numbers for cytokine secretion.
CD3 and Its Impact on Human Health
Dysfunctions within the CD3 complex can affect human health, leading to immune system disorders. Mutations in the CD3 genes, such as CD3D, CD3E, or CD3G, can result in primary immunodeficiencies. These mutations can cause severe combined immunodeficiency (SCID), a condition where T cells are non-functional or absent. For example, a mutation in the CD3D gene prevents the production of the CD3 delta protein, hindering the normal development of T cells. Babies born with CD3 delta SCID are highly susceptible to infections and often do not survive past two years of age without treatment.
In cases of CD3G deficiency, individuals may exhibit immune deficiency or immune dysregulation with autoimmunity, sometimes with delayed onset. Symptoms can include recurrent lung and urinary tract infections, chronic cytomegalovirus infection, and autoimmune conditions like autoimmune cytopenias or severe colitis. Hematopoietic stem cell transplantation (HSCT) is a treatment option for severe cases, alongside supportive measures like immunoglobulin replacement therapy and antimicrobial treatments.
Beyond immunodeficiencies, CD3 proteins serve as diagnostic markers for identifying T cells. Flow cytometry uses the presence of CD3 on cell surfaces to distinguish T cells from other cell types, aiding in diagnosing T-cell leukemias and lymphomas. Immature T cells, such as pro-thymocytes, initially express CD3 in their cytoplasm, which then migrates to the cell membrane as the cells mature. The detection of cytoplasmic CD3 (CyCD3) can therefore indicate immature T-cell malignancies that might not yet express surface CD3.
CD3 also plays a role in modern cancer immunotherapy. Bispecific antibodies target both CD3 on T cells and a specific antigen on tumor cells. These antibodies act as bridges, bringing T cells into close proximity with cancer cells, thereby redirecting the T cells to specifically attack and eliminate tumors, regardless of the T cell’s original antigen specificity. This approach has shown promise, especially in blood cancers, but challenges remain in solid tumors due to factors like limited T-cell infiltration and the immunosuppressive environment around the tumor. Ongoing research explores combination therapies to enhance the effectiveness and safety of CD3-targeting immunotherapies in solid cancers.