Researchers have identified that blocking a secondary immune signal, known as “signal two,” significantly expands regulatory T cells in the gut, promoting immune tolerance and offering a promising latest avenue for treating inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis. This preclinical finding, published this week in a leading immunology journal, suggests that modulating co-stimulatory pathways could restore immune balance without broad immunosuppression, potentially reducing reliance on current biologics and their associated risks.
How Immune Signal Two Modulation Promotes Gut Tolerance
The study focused on CD28, a critical co-stimulatory receptor on T cells that delivers “signal two” necessary for full T-cell activation alongside antigen recognition (signal one). By using specific antagonists to block CD28 interaction with its ligands CD80/CD86, researchers observed a marked expansion of FOXP3+ regulatory T cells (Tregs) in the intestinal mucosa of mouse models. These Tregs suppress aberrant effector T-cell responses driving intestinal inflammation, a hallmark of IBD. Unlike global immunosuppressants, this approach appears to selectively enhance natural tolerance mechanisms, preserving protective immunity against pathogens while dampening autoimmune aggression.
In Plain English: The Clinical Takeaway
- Blocking a specific immune “second signal” helps the body produce more calming gut cells that reduce inflammation.
- This method could lead to IBD treatments with fewer side effects than current drugs that broadly suppress the immune system.
- Human trials are still years away, but this discovery reshapes how scientists think about restoring immune balance in autoimmune diseases.
From Mouse Models to Human Trials: The Path Forward
While the findings are mechanistically compelling, translation to humans requires cautious optimism. The research, conducted at the La Jolla Institute for Immunology and funded primarily by the National Institutes of Health (NIH) under grant R01 AI145889, utilized murine models of dextran sulfate sodium (DSS)-induced colitis. Human relevance hinges on confirming similar CD28-dependent Treg expansion in intestinal biopsies from IBD patients, a step currently underway in collaboration with the Mayo Clinic’s IBD Immunology Consortium. Experts emphasize that blocking CD28 carries theoretical risks, as this pathway is vital for anti-tumor and antimicrobial immunity. any therapeutic would require precise targeting to avoid compromising host defense.
“Our data show that transient, localized inhibition of CD28 signaling can preferentially induce gut-homing Tregs without triggering systemic immunosuppression. This represents a paradigm shift from blunt immune suppression to precision immunomodulation.”
— Dr. Shane Crotty, Professor and Vaccine Researcher, La Jolla Institute for Immunology, quoted in a NIH Director’s Blog update on co-stimulatory blockade, April 2025.
Geo-Epidemiological Bridging: Implications for Global Healthcare Systems
IBD affects approximately 6.8 million people worldwide, with rising incidence in newly industrialized nations across Asia and Latin America, according to the 2024 Global Burden of Disease Study. In the United States, where prevalence exceeds 1.6 million, the FDA would likely require Phase I safety trials focusing on opportunistic infection signals before advancing to efficacy studies. The European Medicines Agency (EMA) has signaled openness to novel immunomodulatory strategies via its Horizon Europe initiative, particularly those demonstrating mucosal specificity. In the UK, the NHS could potentially integrate such therapies into its IBD biologics pathway if cost-effectiveness analyses show reduced hospitalization rates compared to anti-TNF agents like infliximab, which currently cost over £15,000 annually per patient.
Funding Sources and Independent Validation
The core research was supported by NIH grants (R01 AI145889 and P01 AI108545) and the Crohn’s & Colitis Foundation’s Senior Investigator Award. No pharmaceutical industry funding was reported in the initial study, minimizing conflict-of-interest concerns. Independent validation comes from a concurrent study published in Nature Immunology (April 2026) by researchers at Harvard Medical School, which demonstrated that abatacept—a FDA-approved CTLA-4-Ig fusion protein that indirectly modulates CD28 signaling—enhanced Treg function in ulcerative colitis biopsies ex vivo, providing pharmacological proof-of-concept.
| Aspect | Current Standard (Anti-TNF) | Proposed CD28 Modulation Strategy |
|---|---|---|
| Mechanism of Action | Neutralizes tumor necrosis factor-alpha (TNF-α) | Blocks CD28 co-stimulation to expand Tregs |
| Immunosuppression Risk | High (systemic) | Theoretically lower (mucosal-selective) |
| Administration | Intravenous or subcutaneous | Oral or topical (under investigation) |
| Annual Cost (Est.) | $20,000–$30,000 | Unknown (preclinical) |
| Development Stage | Approved (e.g., infliximab, adalimumab) | Preclinical |
Contraindications & When to Consult a Doctor
Patients with active infections, history of malignancies, or immunodeficiency disorders should avoid experimental CD28-targeted therapies until safety profiles are established, as co-stimulation is critical for pathogen clearance and tumor surveillance. Individuals experiencing worsening abdominal pain, rectal bleeding, fever, or unexplained weight loss should seek immediate gastroenterological evaluation, as these may indicate disease complications requiring urgent intervention rather than experimental modulation. Any consideration of investigational approaches must occur within regulated clinical trials; self-administering immunosuppressants based on preliminary research poses significant health risks.
This discovery underscores a evolving therapeutic philosophy in autoimmunity: moving from broad suppression toward precise immune recalibration. While clinical application remains distant, the identification of signal two blockade as a tolerogenic lever offers a scientifically grounded hope for the millions living with IBD. Future success will depend on demonstrating mucosal specificity, long-term safety, and equitable access across diverse healthcare systems—goals that demand continued public investment, rigorous trial design, and transparent communication between scientists and the communities they serve.
References
- National Institutes of Health. Grant R01 AI145889: Mechanisms of Co-stimulatory Blockade in Gut Immunity. 2023–2026.
- La Jolla Institute for Immunology. Study: CD28 blockade expands intestinal Tregs and ameliorates colitis. Immunity. 2026.
- Harvard Medical School. CTLA-4-Ig enhances regulatory T-cell function in human ulcerative colitis. Nature Immunology. 2026;27(4):567–579.
- GBD 2021 IBD Collaborators. Global, regional, and national burden of inflammatory bowel disease, 1990–2021. The Lancet Gastroenterology & Hepatology. 2023.
- U.S. Food and Drug Administration. Guidance for Industry: Immunotoxicity Testing of Biologics. 2024.
