Artificially increasing regulatory T cells offers hope for treating colitis

An international collaborative research group, led by Team Director Ichiro Taniuchi of the Laboratory for Transcriptional Regulation at RIKEN Center for Integrative Medical Sciences and Professor Masahiko Kuroda of the Department of Molecular Pathology at Tokyo Medical University, has elucidated the differentiation control mechanism of antigen-presenting cells that generate peripherally induced regulatory T cells—which are essential for establishing immune tolerance to foreign antigens. The group also demonstrated that artificial manipulation of these cells can increase the number of peripherally induced regulatory T cells. Taniuchi stated, "We would like to utilize our findings to develop methods to suppress rejection reactions in xenotransplantation." The findings were published in the online edition of Nature Immunology.

Regulatory T cells can be classified into two groups: those that differentiate in the thymus, and those that differentiate from naive CD4 cells in peripheral tissues. Peripherally induced regulatory T cells are essential for immune tolerance. Since controlling their differentiation would have significant clinical implications, research and development have been promoted worldwide. However, the cells that present foreign antigen information to naive CD4 cells and make them differentiate into peripherally induced regulatory T cells have not been identified.

More than 20 years ago, Taniuchi had generated mice that lacked Cbfβ2 protein. These mice spontaneously developed colitis at the young age of three months. In recent years, he revealed that the Cbfβ2-deficient mice lacked RORγt-positive pTreg cells because they had defects in the antigen-presenting cells.

Meanwhile, Assistant Professor Chrysothemis Brown and her colleagues at the Memorial Sloan Kettering Cancer Center in the United States had reported that RORγt-expressing Thetis cells (TCs) consisted of four subsets and proposed them as candidates for the antigen-presenting cells that induce the differentiation of peripherally induced regulatory T cells. Taniuchi wondered, "Could these be the cells that are defected in the mice I generated?" He discussed this with Brown at an international conference and started an international collaborative research project.

In their research, they demonstrated that inactivation of Runx1 and Runx3 resulted in the disappearance of peripherally induced regulatory T cells from the intestinal CD4⁺ T cell population and loss of TC-IV among Thetis cells. Furthermore, they revealed that expression of transgenic Runx1 could not only restore TC IV and peripherally induced regulatory T cells but also increase their numbers.

This is the world's first report demonstrating that peripheral regulatory T cells can be increased through artificial intervention. Taniuchi said, "These knockout mice were the ones I first created after becoming an independent researcher. I immediately noticed that these mice spontaneously developed colitis, but I could not determine the cause for a long time. The discovery of peripherally induced regulatory T cells by other researchers and the discovery of Thetis cells in 2022 finally allowed me to identify the cause of their colitis. Our findings hold great potential for therapeutic applications. It is such a great reward for my many years of persistent research."

Journal Information
Publication: Nature Immunology
Title: Runx-CBFβ regulates the development of tolerogenic Thetis cells
DOI: 10.1038/s41590-026-02566-8