CD319 is a protein found on the surface of various cells, playing a role in the complex operations of the immune system. Research into CD319 has shed light on its involvement in immune cell communication and its unexpected connections to certain diseases.
What is CD319
CD319, also known as SLAMF7, CRACC, or CS1, is a protein found on the outer surface of cells. It belongs to the Signaling Lymphocytic Activation Molecule (SLAM) family of receptors, primarily expressed on immune cells. This protein is observed on various immune cells, including Natural Killer (NK) cells, B cells, T cells, dendritic cells, NK-T cells, and monocytes.
The structure of CD319 includes an extracellular domain, which extends outside the cell and interacts with other molecules, and a transmembrane region that anchors it within the cell membrane. It also has an intracellular tail that extends into the cell’s interior. Signaling molecules can attach to this intracellular tail, allowing CD319 to act as a signaling molecule. Several splice variants of CD319 have been identified, with isoform 1 particularly studied for its role in NK cell activation.
How CD319 Works
CD319 functions as a self-ligand receptor, meaning it can bind to itself on opposing cells or even on the same cell, facilitating cell-to-cell communication. This interaction is notable in its influence on Natural Killer (NK) cells, which are lymphocytes capable of recognizing and eliminating infected or abnormal cells. CD319 can either activate or regulate immune cell functions, depending on the specific cell type and the presence of certain internal adapter proteins.
In NK cells, CD319 acts as an activating receptor. Its cytoplasmic tail recruits specific signaling molecules, such as SH2D1B (EAT-2), which become phosphorylated. This phosphorylation initiates downstream signaling pathways, leading to enhanced NK cell activity, degranulation, and improved killing ability against target cells. Conversely, in T cells, where SH2D1B is absent, CD319 can act as an inhibitory receptor, demonstrating its context-dependent roles.
CD319 also influences other immune cells, such as B cells, promoting proliferation and cytokine secretion. In monocytes, CD319 can negatively regulate the production of pro-inflammatory cytokines, suggesting a role in controlling immune responses. The intricate signaling pathways initiated by CD319 highlight its diverse contributions to the regulation of both innate and adaptive immunity.
CD319 and Disease
The expression and function of CD319 are altered in various disease states, particularly in certain cancers. A notable example is multiple myeloma, a cancer of plasma cells in the bone marrow. In this disease, CD319 is highly expressed on the surface of malignant plasma cells, making it a distinctive marker for these cancerous cells.
The overexpression of CD319 on multiple myeloma cells contributes to the disease’s pathology, influencing tumor cell survival and proliferation. This elevated expression has also led to the exploration of CD319 as a diagnostic and prognostic marker for multiple myeloma, with lower expression levels correlating with a better response to treatment. CD319 has been found to be a stable marker, potentially more reliable than traditional markers like CD138 for isolating malignant plasma cells.
While its association with multiple myeloma is well-documented, CD319’s involvement extends to other conditions. Studies have indicated its presence in diseases such as breast cancer, acquired immune deficiency syndrome (AIDS), and systemic lupus erythematosus. In these contexts, CD319 can influence immune cell functions, although the precise mechanisms and contributions to disease progression may vary. The widespread expression of CD319 on various immune cells suggests its broader impact on immune-related disorders beyond cancer.
CD319 as a Therapeutic Target
The distinct expression of CD319 on multiple myeloma cells has positioned it as a target for therapeutic interventions. This understanding led to the development of elotuzumab, a humanized monoclonal antibody designed to specifically bind to CD319. Elotuzumab is marketed under the trade name Empliciti and has been approved for the treatment of relapsed and/or refractory multiple myeloma, used in combination with other agents.
Elotuzumab employs a dual mechanism of action to combat multiple myeloma cells. Primarily, it enhances Natural Killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC). The antibody binds to CD319 on myeloma cells, tagging them, while its Fc portion simultaneously engages with the CD16 receptor on NK cells. This bridges the NK cell to the myeloma cell, prompting the NK cell to release cytotoxic substances, leading to cancer cell death.
Additionally, elotuzumab can directly activate NK cells through its binding to CD319 on the NK cell surface. In NK cells, the presence of the adapter protein EAT-2 allows CD319 engagement by elotuzumab to trigger activating signals, further enhancing the NK cell’s ability to recognize and destroy myeloma cells. This direct activation complements the ADCC mechanism, making elotuzumab a strategy for targeting multiple myeloma.