Interferon gamma

Interferon-gamma (IFN-γ) is a cytokine of the interferon family that plays a central role in the immune response. It is mainly produced by activated T cells (especially Th1 cells) and natural killer cells (NK cells). Interferon-gamma is a key cytokine of cell-mediated immunity that has a strong immunostimulatory and antiviral effect. It plays a decisive role in the defense against intracellular pathogens and in the regulation of the immune response.

Interferon-gamma is a homodimer formed by the non-covalent association of two 17 kDa polypeptide subunits. During synthesis, both subunits bind antiparallel after multiple N-glycosylation and form a mature 50 kDa molecule (Ealick SE et al. 1991). Remarkably, interferon-gamma symmetry suggests that a single molecule can bind to two receptors simultaneously, thereby enhancing the underlying responses. Cellular responses triggered by interferon-gamma may also involve cross-communication with interferon-alpha/gamma receptors, thereby enhancing IFN-γ signaling and its effects (Castro F et al. 2018).

Interferon-gamma is mainly regulated by activated lymphocytes such as CD4 T helper type 1 cells (Th1 cells) and CD8 cytotoxic T cells (Kasahara T et al. (1983) and natural killer cells (NK cells) and to a lesser extent by natural killer T cells (NKT), B cells and professional antigen-presenting cells (APCs) (Castro F et al. 2018). Its expression is induced by mitogens and cytokines such as interleukin-12, interleukin-15, interleukin-18 and type I interferons (the human type I IFN family comprises 17 different proteins, mainly IFN-alpha and IFN-beta/Castro F et al. 2018).

The effects of interferon-gamma are regulated by numerous suppressors and antagonists. Type I IFNs can reduce the production of interferon-gamma, transforming growth factor-beta and interleukin-10 can block the activity of interferon-gamma. Individuals with congenital defects in interferon-gamma immunity are susceptible to various bacterial, mycogenic and protozoal infections (Casanova JL et al. 2024) Autocrine interferon-gamma produced by APCs can act locally, which is critical for early control of pathogen spread, while T lymphocytes are the major paracrine source of interferon-gamma in adaptive immunity. Under physiological conditions, constitutive expression of type I and type II interferons is tightly controlled and remains restricted to tissues without systemic effects.

However, interferon-gamma-mediated signaling can also have suppressive immunoregulatory effects on antiviral, autoimmune and antitumor responses (Castro F et al. 2018).

Therapeutic application: Uncovering cellular targets of interferon-gamma is crucial for its therapeutic application to predict patient response, especially in cancers where this cytokine can exert protumorigenic effects.

Interferon-gamma deficiency: May lead to increased susceptibility to intracellular infections (e.g. genetic defects in the interferon-gamma signaling pathway).

Excessive interferon-gamma production: May increase autoimmune diseases (e.g. rheumatoid arthritis, Crohn's disease) and chronic inflammation.

Interferon-gamma has been used for a long time in chronic granulomatous diseases, leprosy, visceral leishmaniasis, infections with atypical mycobacteria in patients with a lack of CD 4-positive T-cells. It has also been used in rheumatoid arthritis, renal cell carcinoma, melanoma, Schmincke's tumor, CML, hairy cell leukemia, myelodysplastic syndrome and acute leukemia.

1. Casanova JL et al. (2024) Interferon-γ and infectious diseases: Lessons and prospects. Science 384(6693):eadl.
2. Castro F et al. (2018) Interferon-gamma at the Crossroads of Tumor Immune Surveillance or Evasion. Front Immunol 9:847.
3. Ealick SE et al. (1991) Three-dimensional structure of recombinant human interferon-gamma. Science 252:698-702.
4. Kasahara T et al. (1983) Interleukin 2-mediated immune interferon (IFN-gamma) production by human T cells and T cell subsets. J Immunol 130:1784-1789.
5. Ni L et al. (2018) Interferon gamma in cancer immunotherapy. Cancer Med 7:4509-4516.