Butyrophilin’s Role in Immunity, Milk, and Disease

Butyrophilins are a family of proteins first identified for their role in milk production. As part of the immunoglobulin superfamily, they are involved in cell recognition and binding. While initially discovered in the membrane of milk fat globules, butyrophilins are now known to be present in many tissues. Their structure is related to the B7 family of proteins, which are known for immune system communication, hinting at the diverse functions of butyrophilins.

The Role of Butyrophilins in Milk Production

During milk secretion, butyrophilin 1A1 (BTN1A1) is central to the release of large lipid droplets from mammary epithelial cells. BTN1A1 is the most abundant protein in the milk fat globule membrane, the layer encasing fat droplets as they are secreted. Its presence is largely restricted to the mammary gland, with expression increasing at the end of pregnancy and remaining high throughout lactation.

As lipid droplets move to the cell surface for release, BTN1A1 molecules position themselves between the cell’s plasma membrane and the droplet. Interactions involving the cytoplasmic tail of BTN1A1 and other proteins help create a scaffold. This structure stabilizes the fat globule as it is enveloped by the cell membrane and pinched off into the milk. This process ensures the transfer of energy-rich lipids to the newborn.

Butyrophilins and Immune Regulation

Beyond the mammary gland, butyrophilin proteins regulate the immune system. Members like BTN2A2 and the BTN3A subgroup are expressed on various immune cells and modulate T cell activity. These proteins deliver either co-stimulatory or co-inhibitory signals, which helps fine-tune the intensity and duration of an immune response and prevent excessive inflammation.

The BTN3A family activates a subset of T cells known as Vγ9Vδ2 T cells. BTN3A1 and BTN2A1 enable these T cells to recognize phosphoantigens, small molecules that accumulate in infected or malignant cells. The intracellular domain of BTN3A1 senses these phosphoantigens, triggering a change in the protein on the cell surface. This change is detected by Vγ9Vδ2 T cells, leading to their activation and a cytotoxic response against the stressed or cancerous cell.

This regulation is important in mucosal tissues like the gut, where a balanced immune response must tolerate beneficial microbes while fighting pathogens. The expression of butyrophilins on epithelial and antigen-presenting cells in these areas contributes to local immune surveillance. For instance, some butyrophilins can inhibit the signaling that leads to T cell activation, effectively putting a brake on the immune response.

Exploring Butyrophilin-Like (BTNL) Proteins

Butyrophilin-like (BTNL) proteins are a structurally related family that also regulate the immune system. They often act as ligands that bind to receptors on immune cells to modulate their activity. Different BTNL members can have unique and even opposing functions, which is noteworthy for maintaining immune balance within the gut.

Specific BTNL proteins have distinct effects on T cell populations. For example, BTNL2 inhibits T cell activation and proliferation, contributing to immune suppression. In contrast, BTNL8 is a co-stimulatory molecule that enhances the proliferation and cytokine production of activated CD4+ and CD8+ T cells.

Within the intestine, BTNL proteins manage resident lymphocyte populations. For instance, BTNL3 and BTNL8 are expressed by human gut epithelial cells and regulate tissue-specific Vγ4+ T cells. In mice, the proteins Btnl1 and Btnl6 form complexes that promote the maturation of Vγ7+ intraepithelial lymphocytes. These interactions help shape the local immune environment and maintain the mucosal barrier.

Butyrophilins in Health and Disease

The regulatory functions of the butyrophilin and BTNL families mean their dysregulation is associated with diseases ranging from inflammatory conditions to cancer. Genetic variations in these proteins can alter immune responses, leading to excessive inflammation or a failure of immune surveillance. This makes them potential biomarkers and therapeutic targets.

Polymorphisms in the BTNL2 gene are linked to several inflammatory and autoimmune diseases. A specific mutation that truncates the BTNL2 protein is a genetic risk factor for sarcoidosis, a disease involving inflammatory granulomas. Variations in BTNL2 are also associated with increased susceptibility to ulcerative colitis, as the altered protein can disrupt the balance of T cell regulation.

The role of these proteins in cancer is complex, as they can either help or hinder anti-tumor immunity. For instance, the expression of BTNL genes like BTNL2, BTNL3, and BTNL8 is decreased in colon tumors compared to healthy tissue. Conversely, high expression of BTN3A in a tumor can suppress T cell activity, allowing cancer cells to evade the immune system. This has led to therapeutic strategies, such as agonist antibodies that target BTN3A to activate Vγ9Vδ2 T cells and enhance their ability to kill cancer cells.