# Interferon gamma
**Interferon gamma** (IFN-γ, also written IFNG or IFNγ) is a cytokine of the immune system and the sole member of the type II interferon family, produced mainly by T lymphocytes, natural killer cells, and type 1 innate lymphoid cells, that activates macrophages, coordinates antiviral and antimicrobial defense, and shapes adaptive immunity.[1](https://journals.physiology.org/doi/full/10.1152/physrev.00047.2024) • [2](https://pmc.ncbi.nlm.nih.gov/articles/PMC6215902/) It was discovered in 1965 as an antiviral activity in white blood cell cultures stimulated with the lymphocyte mitogen phytohemagglutinin, in work by E. F. Wheelock published in *Science*.[3](https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2014.00667/full)
| Key fact | Detail |
|---|---|
| Family | The only member of the type II interferon family; type I IFNs (IFN-α, IFN-β, IFN-ε, IFN-κ, IFN-ω) and type III IFNs (IFN-λ1 to IFN-λ4) are separate families[1](https://journals.physiology.org/doi/full/10.1152/physrev.00047.2024) |
| Discovery | 1965, as an interferon-like virus-inhibitor induced in human leukocytes by phytohemagglutinin[3](https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2014.00667/full) |
| Gene | The human IFN-γ protein is encoded by a single 6-kb gene on chromosome 12[1](https://journals.physiology.org/doi/full/10.1152/physrev.00047.2024) |
| Receptor | A heterodimer of two transmembrane chains, IFN-γR1 and IFN-γR2, both required for activity; signaling uses Jak1 and Jak2 and the transcription factor STAT1[4](https://pubmed.ncbi.nlm.nih.gov/9208871/) |
| Cellular sources | Only limited subsets of immune cells produce IFN-γ, although its receptor is expressed ubiquitously[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC6215902/) |
| Approved drug | ACTIMMUNE (interferon gamma-1b), subcutaneous injection for reducing the frequency and severity of serious infections in chronic granulomatous disease[5](https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/103836s5182lbl.pdf) |
| Diagnostic use | Interferon-gamma release assays such as QuantiFERON-TB measure IFN-γ released by lymphocytes in whole blood to detect infection with *Mycobacterium tuberculosis*[6](https://www.govinfo.gov/content/pkg/FR-2026-03-30/pdf/FR-2026-03-30.pdf) |
## Discovery and classification
Interferons were originally named for their interfering effect on viral replication. IFN-γ was found in 1965 in mitogen-stimulated leukocyte cultures, later than the type I interferons, and at first was assumed to function strictly as an antiviral like them. Early characterization noted that it was more sensitive than type I IFNs to extremes of pH and to temperatures of 56 °C or higher, an early sign that it was a different kind of interferon.[3](https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2014.00667/full) Interferons are now classified into three types by their cellular receptors: type I, type II, and type III. Type I IFNs can be produced by virtually all cells upon detection of viral or microbial invasion, and type III IFNs are produced by most cells but act on tissue-restricted receptors such as those on mucosal epithelial cells. IFN-γ is the reverse: only limited subsets of immune cells produce it, while its receptor is expressed on essentially all cells.[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC6215902/)
## Receptor and signaling
The IFN-γ receptor consists of two transmembrane chains, IFN-γR1 and IFN-γR2, both of which are required for activity. After ligand binding, the Janus kinases Jak1 and Jak2 are activated by phosphorylation and then phosphorylate the IFN-γR1 chain, which serves as the recruitment site for STAT1 (signal transducer and activator of transcription 1).[4](https://pubmed.ncbi.nlm.nih.gov/9208871/) Activated STATs move into the nucleus and stimulate transcription of specific genes; in interferon signaling they bind either IFN-stimulated response elements (ISREs) or gamma-activated sequences (GASs) on the promoters of interferon-stimulated genes.[7](https://pubmed.ncbi.nlm.nih.gov/30936491/) This JAK/STAT route is shared, with variations, by all interferon types, which is one reason the antiviral gene programs they induce overlap.[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC6215902/)
Signaling is actively restrained. Suppressors of cytokine signaling (SOCS) proteins and regulatory T cells act as governors of IFN-γ signaling, with cross-talk between the two systems in which SOCS1 plays a hierarchical role; too much regulation can be detrimental in diseases such as cancer, while too little can result in autoimmune disease.[3](https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2014.00667/full)
## Sources and immunomodulatory roles
IFN-γ from type 1 innate lymphoid cells (ILC1s) can confer prompt host protection at the initial site of viral infection, while IFN-γ from antigen-activated T lymphocytes establishes an antiviral state and coordinates immune responses for long-term control of infection. Beyond direct effects on infected cells, IFN-γ activates local immune cells such as tissue-resident dendritic cells, macrophages, and NK cells for augmented inflammation and antiviral functions, and it modulates the differentiation and maturation of T cells and B cells.[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC6215902/)
Against non-viral pathogens, IFN-γ is a central macrophage-activating cytokine. It is probably the key cytokine in host defense against *Leishmania* infections, functioning cooperatively with chemokines such as CXCL10 in the CD8+ T cell response to infected cells, and certain gamma/delta T cells produce IFN-γ after *Plasmodium* infection, contributing to dendritic cell reduction of blood-stage malaria parasites.[3](https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2014.00667/full) A 2004 review by Karin Schröder and colleagues in the *Journal of Leukocyte Biology* frames IFN-γ biology around its interplay with macrophages in inflammation and acquired immunity during infection.[8](https://jlb.onlinelibrary.wiley.com/doi/10.1189/jlb.0603252)
## Antiviral mechanisms
In antiviral defense, type I IFNs are predominant, and IFN-γ is less potent as a direct antiviral; one review describes its role during the innate response to virus infection as more supportive, though it induces overlapping intracellular antiviral programs, including PKR.[9](https://pmc.ncbi.nlm.nih.gov/articles/PMC6141705/) Gene expression analysis of virus-infected cells shows overlapping yet not identical gene induction patterns between type I IFNs and IFN-γ, and IFN-γ possesses type I IFN-independent antiviral activity; type I IFNs can even be induced by IFN-γ and contribute to its antiviral effect.[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC6215902/)
**Blocking entry.** IFN-γ can act at the first step of the viral life cycle. It hinders entry of hepatitis C virus by reducing expression of claudin-1 ([CLDN1](https://www.edgepedia.org/cldn1)), a necessary HCV receptor that is particularly upregulated in the HCV-infected liver, and it alters the surface distribution of other HCV receptors, [CD81](https://www.edgepedia.org/cd81) and scavenger receptor class B type I. It also inhibits HIV entry by downregulating surface CD4 on human monocytes.[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC6215902/)
**Metabolic effectors.** IFN-γ is a potent inducer of indoleamine 2,3-dioxygenase (IDO) and nitric oxide synthase (NOS). The resulting depletion of tryptophan and production of nitric oxide show strong antiviral effects, although the molecular details remain mostly unclear.[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC6215902/)
**Non-cytolytic control and latency.** IFN-γ exerts non-cytolytic antiviral activity against several viruses, including hepatitis B virus, measles virus, Sindbis virus, and [West Nile virus](https://www.edgepedia.org/west-nile-virus), with the specific targets and effector proteins largely unknown. It also inhibits the reactivation of murine gamma-herpesvirus 68 from latently infected cells, and against herpes simplex virus 1 it plays a key role in preventing the virus from exiting the latency state.[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC6215902/) • [3](https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2014.00667/full) In most cases it is difficult to separate these direct antiviral effects from IFN-γ's indirect effects through its immunomodulatory activity.[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC6215902/)
## Clinical use
The recombinant drug ACTIMMUNE (interferon gamma-1b) is an injection for subcutaneous use approved to reduce the frequency and severity of serious infections associated with chronic granulomatous disease (CGD), an inherited immune deficiency.[5](https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/103836s5182lbl.pdf) In CGD care it is used for infection prevention alongside life-long antibacterial and antifungal prophylaxis; it does not treat infections or the inflammatory manifestations of the disease, for which no curative therapy exists.[10](https://www.fda.gov/media/188989/download)
IFN-γ also underpins a major diagnostic platform. On November 28, 2001, the FDA approved QuantiFERON-TB, which qualitatively measures IFN-γ generated by human lymphocytes in whole blood in response to stimulation antigens as an aid in detecting infection with *Mycobacterium tuberculosis*; the FDA has since proposed reclassifying this class of interferon-gamma release assays.[6](https://www.govinfo.gov/content/pkg/FR-2026-03-30/pdf/FR-2026-03-30.pdf)
The relationship between IFN-γ and individual viruses can run in both directions. In HIV-1, both therapeutic and exacerbative effects on pathogenesis have been attributed to IFN-γ.[3](https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2014.00667/full)
## References
1. [Type I interferons in health and disease: molecular aspects and clinical implications, Physiological Reviews](https://journals.physiology.org/doi/full/10.1152/physrev.00047.2024)
2. [Direct Antiviral Mechanisms of Interferon-Gamma, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC6215902/)
3. [Johnson HM (2015). Gamma Interferon: From Antimicrobial Activity to Immune Regulation. Frontiers in Immunology](https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2014.00667/full)
4. [The interferon receptors, PubMed](https://pubmed.ncbi.nlm.nih.gov/9208871/)
5. [ACTIMMUNE (interferon gamma-1b) prescribing label, FDA](https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/103836s5182lbl.pdf)
6. [Federal Register Vol. 91 No. 60 (March 30, 2026), Proposed Rules on Mycobacterium tuberculosis interferon-gamma release assays](https://www.govinfo.gov/content/pkg/FR-2026-03-30/pdf/FR-2026-03-30.pdf)
7. [Decoding type I and III interferon signalling during viral infection, PubMed](https://pubmed.ncbi.nlm.nih.gov/30936491/)
8. [Schröder K and colleagues (2004). Interferon-γ: an overview of signals, mechanisms and functions. Journal of Leukocyte Biology](https://jlb.onlinelibrary.wiley.com/doi/10.1189/jlb.0603252)
9. [The Dual Nature of Type I and Type II Interferons, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC6141705/)
10. [Chronic Granulomatous Disease summary for patients, FDA](https://www.fda.gov/media/188989/download)
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*Topic: Encyclopedia › Life and health › Microorganisms and fungi › Viruses and acellular agents › Virus biology and molecular strategies › Virus-host interactions, latency, and oncovirology › Innate antiviral immunity and interferon*
*Initially written Sep 17, 2026 · Reviewed: Sep 30, 2026; Oct 21, 2026 · Edited: Sep 30, 2026; Oct 21, 2026 · Last review: Oct 21, 2026*
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License: Edgepedia Community License 1.0, https://www.edgepedia.org/edgepedia/license