New Research Shows the PTPN22 Gene Doesn’t Actually Boost Interferon Production

A new study from the University of Kansas is shaking up long-held assumptions about the PTPN22 gene, a major genetic factor linked to several autoimmune diseases. For years, scientists believed this gene played a central role in regulating type 1 interferons, the powerful antiviral molecules often described as the immune system’s frontline “workhorses.” But new evidence now shows that this belief was based on flawed earlier research.

This finding matters because millions of people worldwide carry a specific PTPN22 variant—known as R620W in humans—and this variant is strongly associated with conditions like lupus, type 1 diabetes, and many other autoimmune disorders. At the same time, the same gene variant has been connected to improved responses against viral infections and even certain cancers. That made interferons a natural suspect in explaining how one gene could increase disease risk on one hand while providing protection on the other.

The latest study, published in ImmunoHorizons, now provides a much clearer picture of what this gene actually does—and what it doesn’t.

A Long-Standing Hypothesis Put to the Test

For more than a decade, earlier work (much of it based on mouse models) suggested that the PTPN22 mutation increased type 1 interferon production in immune cells. These findings shaped many ideas in immunology, from autoimmune disease mechanisms to potential cancer therapies that might target this gene.

The University of Kansas team set out to verify this interferon link using modern tools and genetically refined animal models. They created CRISPR-Cas9 engineered mice that carried either:

• the PTPN22/PEP risk variant,
• a complete gene knockout, or
• a normal version of the gene.

Their goal was straightforward: repeat the interferon experiments and see whether they could replicate the previously reported effects.

The first surprise came quickly. In the very first experiment—run by an undergraduate researcher—the expected increase in interferon production simply wasn’t there. Thinking it might be a mistake or technical issue, the team repeated the experiments multiple times, across different people and different conditions.

The outcome stayed the same every time: PTPN22 had no measurable effect on type 1 interferon production.

Discovering What Went Wrong in Earlier Studies

After many rounds of replication failure, the team decided to scrutinize the earlier research that had shaped scientific consensus. What they found was revealing.

The mouse strain used in the original studies wasn’t “genetically clean.” In other words, those mice had extra, unintended mutations, unrelated to PTPN22, that influenced the immune system. When the KU scientists recreated experiments using that older strain, they did observe the interferon differences reported years ago. But when they tested their new, genetically precise CRISPR-engineered mice, those differences disappeared.

This discovery showed that much of the past understanding of PTPN22 and interferon production was likely a false signal caused by genetic background noise, not a true biological effect of the PTPN22 gene.

What the Gene Does Influence

Even though interferon production wasn’t affected, the researchers found that PTPN22 still plays meaningful roles in the immune system. Instead of interferons, the gene influenced other cytokines—immune signaling molecules that help coordinate how immune cells communicate.

In their experiments, knocking out the PTPN22 gene changed levels of TNF, IL-12, and other important cytokines in myeloid cells. That means the gene is still involved in immune regulation, just not in the way scientists had previously thought.

Understanding exactly how PTPN22 shapes immune responses is crucial not only for decoding autoimmune disease risk but also for designing therapies. The research team emphasized that clarifying the gene’s real function helps researchers avoid wasted effort pursuing incorrect pathways and instead focus on mechanisms that actually matter.

Why This Matters for Autoimmunity, Cancer, and Infection

The PTPN22 R620W variant is one of the strongest known genetic predictors of autoimmune disease. People who inherit this variant have a significantly higher risk for conditions including:

• Systemic lupus erythematosus
• Type 1 diabetes
• Rheumatoid arthritis
• Multiple other autoimmune disorders

Yet, intriguingly, both human and mouse studies have shown that individuals with the same variant are often better at fighting viral infections and have enhanced anti-tumor immunity, especially against cancers like melanoma.

For years, interferons seemed like the perfect explanation for this paradox—more interferons could plausibly mean better antiviral defense but also higher risk of immune overreaction.

With interferons now ruled out, scientists will need to reevaluate how this gene shapes both autoimmune risk and protective immunity. The new evidence points toward other cytokines and cell-signaling pathways as more likely candidates.

Implications for Drug Discovery

PTPN22 has long been considered a potential target for new immune-modulating drugs, especially in cancer research. The KU team is already collaborating with Johns Hopkins and Purdue University to explore small-molecule inhibitors of PTPN22—medications that could potentially amplify immune responses against tumors.

The new findings give these efforts a clearer foundation. Any drug development strategy must be based on what the gene actually does, not what scientists assumed it did in the past.

Their study also revealed something encouraging: knocking out the PTPN22 gene in mice that are otherwise resistant to autoimmunity did not produce harmful side effects. However, in mice that are genetically predisposed to autoimmune conditions, removing the gene did accelerate autoimmune reactions. This suggests that targeting PTPN22 could be safe in some individuals but risky in others, especially those already susceptible to autoimmune disease.

Understanding PTPN22 Beyond This Study

Since this news is deeply tied to the biology of PTPN22, here are some additional details about the gene that help put the findings into context.

PTPN22’s Role in Immune Signaling

PTPN22 encodes an enzyme called a protein tyrosine phosphatase, which acts like a brake in immune cell signaling. It helps regulate how strongly T cells and B cells respond to stimulation. When this control system is altered—as in the R620W variant—immune cells may react more intensely or inappropriately.

Why the R620W Variant Increases Autoimmunity Risk

One key effect of this mutation is impaired B-cell tolerance. People carrying the variant often show higher numbers of autoreactive B cells, meaning their immune system is more likely to produce antibodies that mistakenly attack the body.

How the Mutation May Improve Anti-Cancer Immunity

Enhanced immune activation—while dangerous in autoimmunity—can be helpful when fighting cancer. A more reactive immune system can recognize and destroy tumor cells more effectively.

This duality explains why PTPN22 is such an important gene in immunology: it highlights how small genetic changes can shift the immune system’s balance between protection and self-damage.

A Study That Corrects Course for the Field

The main takeaway from this research is its clarity. By revisiting a widely accepted assumption with more rigorous tools and cleaner models, the KU team has corrected a major misunderstanding in immunology. Scientists now have a more accurate foundation for exploring PTPN22’s real role, whether in basic research or in the development of future therapies.

The study doesn’t diminish the importance of PTPN22. Instead, it refocuses attention on the mechanisms that actually matter and opens new questions that could bring the field closer to understanding—and eventually treating—complex immune-related diseases.

Research Paper Reference

Type I interferon production in myeloid cells is regulated by factors independent of Ptpn22
https://doi.org/10.1093/immhor/vlaf063