Osaka University find that exacerbation of autoimmune neurological diseases suppressed by regulatory T cells

A research group led by Project Researcher Masaaki Okamoto (at the time of the study) and Professor Masahiro Yamamoto of the Research Institute for Microbial Diseases at Osaka University has announced their research results showing that helper T cells (Th)1-regulatory T cells (Tregs) (Th1-Tregs) suppress exacerbation of autoimmune neurological diseases, such as multiple sclerosis, through accumulation in lesions. They analyzed an animal model of multiple sclerosis in which only Th1-Tregs were removed (experimental autoimmune encephalomyelitis [EAE] mice). Interferon-gamma (IFN-γ) secreted by T cells was found to induce differentiation into Th1-Tregs and suppress inflammation. The results were published in the Proceedings of the National Academy of Sciences of the United States of America PNAS on November 19.

Multiple sclerosis is an autoimmune disease in which the immune system attacks and destroys the myelin sheaths that surround nerve fibers. It is estimated to affect about 19,000 people in Japan. Tregs have a function to suppress Th cells and are known to include subpopulations targeting different Th cell subsets, such as Th1-Tregs. Cancer therapy with anti-CTLA-4 antibodies, which increase immune activity against cancer by suppressing Treg function, has been challenged by the development of autoimmune diseases as a side effect. In 2023, the research group developed a VeDTR mouse system in which cells characterized by two different genes can be specifically labeled and removed. They demonstrated that cancer treatment with anti-CTLA-4 antibodies is possible by removing only Th1-Tregs to thereby suppress the immune system. Meanwhile, it was unclear whether Th1-Tregs are involved in induced autoimmune diseases such as multiple sclerosis.

In the present study, the research group induced EAE in VeDTR mice and examined the localization of Th1-Tregs in the brain. They found that Th1-Tregs were highly accumulated in demyelinated areas in the brain. The mechanistic investigation revealed the importance of IFN-γ, an inflammatory cytokine, for converting Tregs to Th1-Tregs in the brain. The research group also found that EAE was exacerbated by removing Th1-Tregs in EAE mice.

These findings indicate that in neurological diseases such as EAE, Th1-Tregs suppress autoimmunity, which is responsible for neuronal demyelination in the brain. Depletion of Th1-Tregs may exacerbate multiple sclerosis in cancer patients with multiple sclerosis. It was found that removal of Th1-Tregs for cancer treatment should be performed in a tumor-specific manner.

Journal Information
Publication: PNAS
Title: IFN-γ-induced Th1-Treg polarization in inflamed brains limits exacerbation of experimental autoimmune encephalomyelitis
DOI: 10.1073/pnas.2401692121