Interferon gamma (IFN-γ) is a protein crucial for the body’s defense system. It coordinates responses against viruses, bacteria, and cancer cells. It acts as a communication signal, enabling immune cells to work together. Its presence is linked to fighting infections and overall well-being.
What is Interferon Gamma?
Interferon gamma belongs to a group of signaling proteins called cytokines, molecular messengers within the immune system. It is classified as a Type II interferon and is distinct from other interferon types, such as Type I interferons (alpha and beta). Primary cells producing IFN-γ include T lymphocytes (T helper 1 and cytotoxic T cells) and natural killer (NK) cells. Other immune cells like natural killer T (NKT) cells, B cells, and antigen-presenting cells also produce it.
IFN-γ is a soluble protein that exists as a homodimer. This structure allows it to bind to two receptors simultaneously, enhancing signaling. Its production is triggered by immune signals like interleukins (IL-12, IL-15, IL-18) and Type I interferons, particularly during infections or tissue damage. IFN-γ facilitates communication among immune cells, helping them coordinate responses to pathogens and abnormal cells.
How Interferon Gamma Signals
Interferon gamma communicates with cells by binding to specific receptors. This receptor, known as the IFN-γ receptor (IFN-γR), is composed of two subunits, IFN-γR1 and IFN-γR2. Both subunits are required for the cell to respond to IFN-γ.
When IFN-γ binds to its receptor, it causes receptor dimerization. This activates associated Janus kinases (JAKs), specifically JAK1 and JAK2. Once activated, these JAKs add phosphate groups to the receptor and to Signal Transducers and Activators of Transcription (STATs), particularly STAT1. This phosphorylation allows STAT1 to form homodimers, which then detach from the receptor.
These STAT1 homodimers then travel into the cell’s nucleus, where they bind to specific DNA sequences in gene promoter regions. These sequences are called gamma interferon-activated sites (GAS). This binding initiates changes in gene expression, leading to new proteins that alter cell behavior and function. This process, known as the JAK-STAT pathway, directly turns on specific genes, orchestrating a targeted cellular response.
Its Roles in Immunity
Interferon gamma signaling plays diverse roles in immunity. It is a potent activator of macrophages, enabling these immune cells to enhance their ability to destroy microbes within them. This activation involves increasing their capacity for phagocytosis, which is the process of engulfing and breaking down pathogens, and boosting their nonspecific activity against microbial targets and tumors. IFN-γ also stimulates macrophages to produce more pro-inflammatory cytokines.
In antiviral defense, IFN-γ directly inhibits viral replication. It also alerts other immune cells, such as natural killer cells, promoting their activity. For antibacterial immunity, IFN-γ is particularly important for combating intracellular pathogens, which are bacteria that live inside host cells. It helps activate macrophages to effectively eliminate these internal threats.
IFN-γ also contributes to anti-tumor immunity by helping immune cells recognize and eliminate cancer cells. It promotes the activity of T helper 1 cells, cytotoxic T cells, natural killer cells, and dendritic cells. IFN-γ enhances antigen presentation, a process where immune cells display fragments of pathogens or tumor cells to other immune cells, thereby improving immune recognition and response. It also influences the differentiation of T cells into specific subtypes, such as Th1 effector T cells, which are important for orchestrating immune responses against various pathogens.
Interferon Gamma in Disease and Treatment
Dysregulation of interferon gamma signaling, either too much or too little, can contribute to various health conditions. Excessive or misdirected IFN-γ activity is implicated in autoimmune diseases, where the immune system mistakenly attacks the body’s own tissues. Examples include rheumatoid arthritis and multiple sclerosis, where sustained IFN-γ signaling can lead to chronic inflammation and tissue damage. In chronic infections, prolonged IFN-γ production can also contribute to pathology and tissue damage.
Conversely, insufficient IFN-γ signaling can lead to immunodeficiency, making individuals more susceptible to infections. Chronic granulomatous disease (CGD) is an inherited immunodeficiency where phagocytes, a type of immune cell, have a reduced ability to destroy pathogens. In such cases, recombinant human IFN-γ has been used as a medication to reduce the frequency and severity of serious infections. Clinical trials have shown that administering IFN-γ can improve the bactericidal capacity of neutrophils in CGD patients.
Beyond genetic disorders, IFN-γ also shows promise in cancer immunotherapies. Its ability to activate various immune cells, promote antigen presentation, and directly inhibit tumor cell proliferation makes it a target for enhancing anti-cancer immune responses. While IFN-γ can have complex effects within the tumor microenvironment, its potential to promote tumor cell killing and enhance T cell-mediated anti-tumor immunity is being explored in therapeutic strategies.