Development of iTreg Cell Therapy for Inflammatory and Autoimmune Diseases

The 2025 Nobel Prize in Physiology or Medicine was awarded to Mary Brunkow, Fred Ramsdell, and Shimon Sakaguchi for their discovery and definition of regulatory T cells (Treg cells), revealing their importance in controlling autoreactive responses and pioneering the new field of Treg cell-mediated peripheral immune tolerance.

In 1995, Shimon Sakaguchi published a paper in The Journal of Immunology, discovering a previously unknown type of T cell (T cells expressing CD4 and CD25) that protects the body from autoimmune diseases. In 2001, Mary Brunkow and Fred Ramsdell published three papers in Nature Genetics, discovering that mutations in the Foxp3 gene lead to autoimmune diseases in both mice and humans. In 2003, Shimon Sakaguchi connected these findings, publishing a paper in Science demonstrating that the Foxp3 gene controls the development of the immune cells he discovered in 1995 (i.e., Treg cells). These Treg cells monitor other immune cells and ensure that our immune system tolerates our own tissues.

Their groundbreaking discoveries have opened new doors for the treatment of autoimmune diseases and cancer. For example, we can use Treg cells specifically targeting self-antigens to suppress pathogenic autoimmune responses in patients, preventing the immunosuppression problems caused by conventional cell therapies that broadly affect the immune system. However, isolating a sufficient number of naturally occurring self-antigen-specific Treg cells from patients remains a significant challenge.

In October 2025, Shimon Sakaguchi's team published two papers in Science Translational Medicine, a sub-journal of Science, successfully inducing conventional effector T cells into functionally stable regulatory T cells (S/F-iTreg cells) using cytokines and drugs for cell therapy of inflammatory diseases (inflammatory bowel disease, graft-versus-host disease) and autoimmune diseases (pemphigus vulgaris).

The first paper is titled "Generating functionally stable and antigen-specific Treg cells from effector T cells for cell therapy of inflammatory diseases". A key strategy for antigen-specific immunosuppression is to convert antigen-specific conventional T cells (Tconv) into Foxp3+ regulatory T cells (Treg) to achieve stable suppressive function comparable to natural regulatory T cells (nTreg). In this latest study, the research team achieved high Foxp3 expression in Tconv cells under antigen and IL-2 co-stimulation conditions by treating them with CDK8/19 kinase inhibitors in in vitro cell experiments using both mouse and human cells.

The research team further established Treg cell-specific epigenetic changes by depriving CD28 co-stimulation during in vitro induction of Treg cells, thereby specifically promoting the expression of Treg cell characteristic genes, especially Foxp3. By repeating this process and using a culture medium containing only IL-2 during the intermittent periods, they successfully reprogrammed effector/memory CD4+ Tconv cell subsets (including TH1, TH2, and TH17 cells) into Foxp3+ Treg cells. These induced functionally stable regulatory T cells (S/F-iTreg cells) were similar to natural regulatory T cells (nTreg cells) in terms of transcriptional and epigenetic modifications, and were functionally and phenotypically stable in vivo.

Figure 1. S/F-iTreg cells can be generated from effector/memory CD4+ Tconv cells. (Mikami N, et al., 2025)

The research team further confirmed that iTreg cells effectively suppressed inflammatory bowel disease (IBD) and graft-versus-host disease (GvHD) in mouse models. This study suggests that adoptive cell therapy using these functionally stable iTreg cells induced from effector/memory conventional T cells may represent a new strategy for achieving antigen-specific and disease-specific treatment of immune diseases.

The second paper is titled "Conversion of pathogenic T cells into functionally stabilized Treg cells for antigen-specific immunosuppression in pemphigus vulgaris". Pemphigus vulgaris is a skin autoimmune disease mediated by anti-Dsg3 autoantibodies. This study converted Dsg3-specific pathogenic autoreactive CD4+ T cells into functionally stable Foxp3+ Treg cells in vitro, naming them S/F-iTreg cells.

The research team further demonstrated the therapeutic effect of S/F-iTreg cells in a mouse model of pemphigus vulgaris and provided proof-of-concept data showing that S/F-iTreg cells can be generated from cells of human patients with pemphigus vulgaris. This represents a significant step forward in advancing this S/F-iTreg cell generation platform towards clinical application.