A study published on June 9, 2025, in Diabetologia revealed that T cells and autoantibodies in individuals with type 1 diabetes (T1D) can recognize proteins that ordinarily reside within the cell nucleus and are found in cells throughout the body — suggesting a systemic autoimmune component in this organ-specific disease. Researchers at Benaroya Research Institute (BRI), in collaboration with colleagues in Worcester, Massachusetts, and Germany, identified specific CD4+ T cells and antibody responses targeting the nuclear proteins NUP50 and MLH1, deepening our understanding of immune tolerance breakdown in T1D.
T1D is an autoimmune disease in which insulin-producing cells in the pancreas, called beta cells, are destroyed by self-reactive immune cells. Insulin-specific autoantibodies are known to be present even before clinical manifestation or diagnosis of the disease, however, 15% of T1D patients don’t exhibit the typical beta-cell autoantibodies. Thus, researchers are interested in identifying other relevant autoimmune targets that could be directing beta cell destruction, especially in the absence of the islet autoantibodies. This new study shows that the immune system of individuals with T1D recognizes two nuclear proteins, called NUP50 and MLH1, which are normally found inside the nucleus of many different types of cells throughout the body.
“Historically, T1D has been considered a pancreas-specific autoimmune disease, but this study indicates a broader autoimmune response may be at play,” said Eddie James, PhD, principal investigator at BRI.
The research team studied blood samples and pancreatic tissue from people with T1D and found that CD4+ T cells recognizing MLH1 and NUP50 were significantly more abundant in individuals with T1D compared to healthy controls. Notably, these T cells also appeared in the pancreatic islets of organ donors with the disease, demonstrating their relevance at the site of immune attack.
Both proteins had been previously identified in other studies, but their recognition by disease-relevant T cells had not been established until now. Importantly, although antibody and T cell responses to these nuclear targets co-occurred in some individuals, their relationship was not always straightforward — some people had both, while others had only one type of response. This highlights a complex immune response in autoimmunity that can vary from person to person.
“T1D remains a complex and multifaceted disease,” noted Carla Greenbaum, MD, director of the Center for Interventional Immunology at BRI. “By identifying novel T cell targets and mapping their presence in the pancreas, we are one step closer to understanding how self-tolerance is broken and how we might intervene earlier in the disease process.”
This research underscores the importance of continued exploration of lesser-known autoantigens and adds an important piece to the puzzle of T1D. Futures studies will investigate how these nuclear proteins that are nonspecific to the pancreas contribute to the breakdown of immune tolerance to beta cells, further illuminating the mechanism of autoimmunity in diseases like T1D.
