A new strategy for immune tolerance

2025-12-22

(Press-News.org)

A research team at the Nano Life Science Institute (WPI-NanoLSI) and the Faculty of Medicine at Kanazawa University has developed a new class of engineered extracellular vesicles (EVs) capable of inducing antigen-specific regulatory T cells (Tregs), the immune cells that play a central role in suppressing excessive immune responses. The findings, now published in Drug Delivery, may pave the way for next-generation therapies for autoimmune and allergic diseases, where unwanted immune activation must be precisely controlled.

Autoimmune diseases arise when the immune system mistakenly attacks the body’s own tissues. Current treatments largely rely on broad immunosuppression using steroids or immunosuppressants, which reduce symptoms but also weaken protective immunity, leaving patients vulnerable to severe infections and other complications. A long-standing goal in immunology has been the development of therapies that suppress immune responses only toward disease-related antigens, a concept known as “antigen-specific immune tolerance.”

Regulatory T cells (Tregs) represent the body’s natural mechanism for maintaining immune tolerance, but inducing antigen-specific Tregs safely and efficiently in vivo has proven extremely difficult. To address this challenge, Shota Imai, Tomoyoshi Yamano and Rikinari Hanayama, and colleagues engineered “antigen-presenting extracellular vesicles” (AP-EVs-Treg) that display, on a single vesicle surface, peptide–MHC class II complexes (pMHCII) for antigen-specific T-cell recognition together with the two cytokines interleukin-2 (IL-2) and transforming growth factor-β (TGF-β), both of which are essential for Treg differentiation.

Strong induction of functional, antigen-specific Tregs in vitro
When AP-EVs were co-cultured with naïve CD4⁺ T cells from antigen-specific TCR-transgenic mice, they efficiently induced the differentiation and expansion of Foxp3⁺ Tregs. These induced Tregs expressed high levels of suppressive molecules such as CTLA-4, PD-L1, and LAG-3, and potently inhibited the proliferation of other T cells in a dose-dependent manner, demonstrating robust suppressive function.

Importantly, AP-EVs could be adapted to load different disease-related antigens, including MOG peptides associated with multiple sclerosis, enabling the induction of antigen-specific Tregs relevant to autoimmune pathology.

In vivo Treg induction enhanced by mTOR inhibition
In animal models, AP-EVs selectively activated antigen-specific CD4⁺ T cells based on their pMHCII specificity. However, Foxp3 induction required the co-administration of rapamycin, an mTOR inhibitor known to promote Treg differentiation. The combination of AP-EVs and rapamycin markedly increased the generation of antigen-specific Tregs in vivo, highlighting a synergistic mechanism and revealing a promising strategy for restoring immune tolerance in physiological environments.

A modular and clinically adaptable immune-tolerance platform
Unlike mRNA or nanoparticle-based tolerogenic systems, EVs are naturally derived, highly biocompatible, and capable of presenting multiple functional molecules simultaneously with low immunogenicity. The modularity of AP-EV design allows tuning of antigen specificity and immunoregulatory signals, opening the door to future applications such as autoimmune diseases and allergic diseases.

Background
Autoimmune diseases occur when immune cells mistakenly recognize self-derived molecules as threats. More than 80 autoimmune disorders have been identified, affecting hundreds of millions of people worldwide. Current immunosuppressive therapies are non-specific and rarely produce long-term remission.

Antigen-specific regulatory T cells (Tregs) represent a promising therapeutic approach because they can selectively suppress only the disease-relevant immune responses while preserving protective immunity. However, safely generating such Tregs within patients remains a major technological challenge.

Engineered extracellular vesicles (EVs) offer a unique platform due to their natural biocompatibility, low immunogenicity, and ability to display multiple functional molecules. The AP-EV system developed by the Kanazawa University research team is the first EV-based platform to simultaneously deliver pMHCII, IL-2, and TGF-β, the essential triad required for antigen-specific Treg induction.

Funding
This work was supported by Japan Society for the Promotion of Science (JSPS) KAKENHI (Grant Number 24KJ1187-00 to SI), Doctoral Program for World-leading Innovative & Smart Education (WISE) Program for Nano-Precision Medicine to SI, Japan Science and Technology Agency (JST) Precursory Research for Embryonic Science and Technology (PRESTO) (No. JPMJPR19HA to TY), JST Fusion Oriented Research for Disruptive Science and Technology (FOREST) (No. JPMJFR2115 to TY), Practical Research for Innovative Cancer Control from the Japan Agency for Medical Research and Development (AMED) (No. 24ck0106967h0001 to TY). Science and Technology Platform for Advanced Biological Medicine from AMED (No. 22am0401019h0004 to RH).

Contact
Kimie Nishimura (Ms)
Project Planning and Outreach, NanoLSI Administration Office
Nano Life Science Institute, Kanazawa University
Email: nanolsi-office@adm.kanazawa-u.ac.jp
Kakuma-machi, Kanazawa 920-1192, Japan

Nano Life Science Institute (WPI-NanoLSI), Kanazawa University
Understanding nanoscale mechanisms of life phenomena by exploring “uncharted nano-realms.” Cells are the basic units of life. At NanoLSI, researchers develop nanoprobe technologies that enable direct imaging, analysis, and manipulation of biomolecules such as proteins and nucleic acids inside living cells. By visualizing these processes at the nanoscale, the institute seeks to uncover fundamental principles of life and disease.

https://nanolsi.kanazawa-u.ac.jp/en/

About the World Premier International Research Center Initiative (WPI)
The WPI program was launched in 2007 by Japan’s Ministry of Education, Culture, Sports, Science and Technology (MEXT) to foster world-class research centers with outstanding research environments. WPI centers enjoy a high degree of autonomy, enabling innovative management and global collaboration. The program is administered by the Japan Society for the Promotion of Science (JSPS).

WPI News Portal: https://www.eurekalert.org/newsportal/WPI　
Main WPI program site: www.jsps.go.jp/english/e-toplevel　

About Kanazawa University
Founded in 1862 in Ishikawa Prefecture, Kanazawa University is one of Japan’s leading comprehensive national universities with a history spanning more than 160 years. With campuses at Kakuma and Takaramachi–Tsuruma, the university upholds its guiding principle of being “a research university dedicated to education, while opening its doors to both local and global society.”

Internationally recognized for its research institutes, including the Nano Life Science Institute (WPI-NanoLSI) and the Cancer Research Institute, Kanazawa University promotes interdisciplinary research and global collaboration, driving progress in health, sustainability, and culture.
http://www.kanazawa-u.ac.jp/en/

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A new strategy for immune tolerance

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