Butyrophilin: Protein Function and Impact on Health
Explore the butyrophilin protein family, from their role in metabolic processes to their influence on immune cell communication and its implications for human health.
Butyrophilins are a group of proteins first identified for their role in milk production. Discovered within the membranes surrounding fat droplets in milk, they were named for this association with butterfat. Subsequent research has revealed that their functions extend far beyond lactation to encompass a wide range of biological processes, particularly within the immune system. This discovery has made butyrophilins a subject of growing scientific interest.
Understanding the Butyrophilin Family
The term butyrophilin refers to a large family of related proteins, broadly classified into Butyrophilin (BTN) and Butyrophilin-like (BTNL) subfamilies. The genes that code for these proteins in humans are clustered on chromosome 6 within the major histocompatibility complex (MHC), a region of the genome important for immune function.
Structurally, butyrophilins are type 1 transmembrane proteins, meaning they pass through a cell membrane once. Their architecture includes extracellular portions with immunoglobulin (Ig)-like domains, which are structures involved in recognition and binding on the cell surface. This structural similarity to other immune-regulating families, like the B7 proteins, suggests a capacity for signaling with immune cells. The proteins also feature a cytoplasmic tail that transmits signals into the cell.
Butyrophilins in Milk Fat Secretion
The primary role of the protein BTN1A1 is in the secretion of fat from mammary gland cells during lactation. Milk provides a complete source of nutrition for a nursing infant, and much of its energy is delivered as fats. These fats are synthesized within the epithelial cells of the mammary gland as lipid droplets, which are then exported into the milk.
The secretion process involves BTN1A1 in the final step of enveloping these lipid droplets in a layer of the cell’s membrane. As lipid droplets move to the cell’s edge, BTN1A1 helps organize the membrane wrapping process, ensuring the droplet is fully encased before it buds off. This creates the milk fat globule (MFG), a structure that protects the fat and aids its digestion.
Impact on Immune Responses
Beyond lactation, butyrophilins are regulators of the immune system. Many BTN and BTNL proteins function as co-signaling molecules that can either inhibit or stimulate the activity of immune cells. They are expressed on the surface of various immune cells, like lymphocytes and dendritic cells, and on epithelial cells in tissues like the gut.
Their regulatory activity affects both the innate and adaptive branches of the immune system. For example, certain butyrophilins can suppress the activation of T cells, a type of white blood cell. Proteins like BTN1A1 and BTNL2 have been shown to inhibit the activity of CD4+ and CD8+ T cells and reduce their production of inflammatory cytokines. Conversely, other members like BTNL8 can enhance T cell proliferation.
Some butyrophilins, such as BTN3A1, play a specialized role in activating gamma delta (γδ) T cells. These cells are abundant in tissues like the intestinal lining and are important for recognizing signs of cellular stress from cancer or infection. BTN3A1 presents specific molecules called phosphoantigens, which accumulate in unhealthy cells, to the Vγ9Vδ2 T cell receptor, triggering these immune cells to eliminate the threat.
Butyrophilins and Human Health
Because they regulate immune responses, alterations in butyrophilin genes or their expression levels are linked to a range of medical conditions. Genetic variations in certain BTN and BTNL genes are associated with an increased risk for autoimmune and inflammatory disorders, including inflammatory bowel disease (IBD), multiple sclerosis, and rheumatoid arthritis.
In cancer, the role of butyrophilins is complex. Some butyrophilins, by inhibiting T cell function, may allow tumors to evade detection by the immune system. However, other family members are involved in activating anti-tumor immune responses. For instance, a high level of BTN3A2 expression in certain ovarian cancers is associated with a better prognosis.
The involvement of these proteins in disease makes them promising candidates for medical applications. Researchers are exploring their potential as biomarkers to help in the diagnosis or prognosis of certain diseases. Because of their ability to modulate immune cell activity, butyrophilins are also being investigated as therapeutic targets for treating autoimmune diseases and cancer.