Interleukin 12 receptor

The Interleukin 12 receptor (IL-12R) is a type I cytokine receptor that is primarily expressed on the surface of natural killer cells, T lymphocytes, and other immune cells. It plays a crucial role in the immune response by mediating the effects of interleukin 12 (IL-12), a cytokine that is essential for the differentiation of naive T cells into Th1 cells.

Structure

The IL-12 receptor is a heterodimeric complex composed of two subunits: the IL-12Rβ1 and IL-12Rβ2 chains.

IL-12Rβ1 Subunit

The IL-12Rβ1 subunit is encoded by the IL12RB1 gene located on chromosome 19. It is a type I transmembrane protein that contains an extracellular domain, a single transmembrane helix, and a cytoplasmic tail. The extracellular domain is responsible for binding to the p40 subunit of IL-12.

IL-12Rβ2 Subunit

The IL-12Rβ2 subunit is encoded by the IL12RB2 gene located on chromosome 1. It is also a type I transmembrane protein with a similar structure to IL-12Rβ1. The IL-12Rβ2 subunit is primarily responsible for signal transduction upon IL-12 binding.

Function

The primary function of the IL-12 receptor is to mediate the biological effects of IL-12. Upon binding of IL-12 to its receptor, a signaling cascade is initiated that leads to the activation of Janus kinase 2 (JAK2) and tyrosine kinase 2 (TYK2), which in turn phosphorylate and activate signal transducer and activator of transcription 4 (STAT4). Activated STAT4 translocates to the nucleus and induces the expression of genes involved in the differentiation of Th1 cells and the production of interferon gamma (IFN-γ).

Role in Immune Response

IL-12 and its receptor are critical for the development of Th1 responses, which are essential for the defense against intracellular pathogens such as viruses and certain bacteria. Th1 cells produce IFN-γ, which activates macrophages and enhances their ability to kill ingested microbes. The IL-12/IL-12R axis is also involved in the activation and proliferation of natural killer cells, which play a role in the early defense against infections and in tumor surveillance.

Clinical Significance

Mutations in the IL12RB1 gene can lead to immunodeficiency due to impaired IL-12 signaling. Patients with such mutations may present with increased susceptibility to mycobacterial and salmonella infections. Additionally, dysregulation of IL-12 and its receptor has been implicated in various autoimmune diseases, such as multiple sclerosis, Crohn's disease, and psoriasis.

Therapeutic Implications

Targeting the IL-12/IL-12R pathway has therapeutic potential in treating autoimmune diseases and certain types of cancer. Monoclonal antibodies that block IL-12 or its receptor are being investigated as treatments for these conditions. Conversely, enhancing IL-12 signaling may boost immune responses in cancer immunotherapy.

See Also

• Interleukin 12
• Cytokine receptor
• Th1 cells
• Signal transducer and activator of transcription 4