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Roughly 9.5 million individuals worldwide contend with Type 1 diabetes, a persistent autoimmune condition wherein T cells from the body’s immune response eliminate insulin-producing cells located in the pancreas, which are essential for regulating blood sugar levels. Regular insulin injections along with continuous blood glucose monitoring aid in managing the condition; however, a remedy or prevention method remains elusive.
Currently, scientists at Washington University School of Medicine in St. Louis have discovered a cohort of immune cells in the pancreas capable of rendering T cells inactive, thus safeguarding insulin-releasing beta cells and thwarting the development of Type 1 diabetes in mice that would otherwise be predisposed to the condition. The recently identified cells are a variety of macrophage—immune cells that engulf dead cells throughout the organism to support tissue health.
The investigators disclosed that the defensive macrophages, which they referred to as efferocytic macrophages, or eMacs, acquired the capability to deactivate T cells following the consumption of dead cells in the pancreas.
The research is published in Nature on Oct. 1.
“We have now identified the cells that can diminish T cell reactivity,” stated senior author Kodi Ravichandran, PhD, the Robert L. Kroc Professor of Pathology & Immunology and a BJC Investigator at WashU Medicine. “If we can replicate the sequence of events that transforms macrophages into e-Macs, we might enhance them to assist in preventing or managing Type 1 diabetes, as well as other autoimmune disorders.”
Waste-consuming immune cells provide protection
The pancreas houses clusters of beta cells responsible for insulin production, a hormone vital for maintaining blood sugar levels within a safe range. A small proportion of beta cells typically perish to mitigate inflammation and preserve tissue health, a natural occurrence that transpires in cells across the body.
Macrophages subsequently engulf and process the cellular remnants in a procedure referred to as efferocytosis. These waste-eating cells also significantly influence T cell behavior throughout the system. The researchers questioned whether these macrophages contribute to preserving pancreatic tissue health by modulating the immune response.
“The manner in which macrophages interact with and consume cellular waste can shape the dynamics within the cellular environment,” commented Ravichandran. “This also affects how macrophages engage with T cells.”
For instance, macrophages can stimulate T cells to combat an infection after ingesting a dying infected cell. In the scenario involving naturally dying beta cells in the pancreases of mice, the researchers discovered that post-ingestion, the eMacs altered their behavior to deactivate T cells, thereby safeguarding the surrounding healthy beta cells from harm. The team hypothesized that the macrophages essentially adopted this behavior after consuming the deceased beta cells and that if this process could be replicated, then the healthy beta cells might be shielded from T cell assault in the context of diabetes.
In their study, the researchers administered a single low dosage of a chemotherapy agent, streptozotocin, to mice predisposed to Type 1 diabetes in an experiment designed to eliminate a few cells in the pancreas, mimicking the natural cell death process that occurs in healthy individuals to maintain organ health. They identified a higher proportion of e-Macs among the macrophages in the pancreases of streptozotocin-treated mice compared to those in the placebo group. Mice treated with streptozotocin were shielded from developing diabetes for over 40 weeks, while those receiving the placebo developed diabetes by 20 weeks and did not survive beyond 30 weeks.
The researchers aspire to discover methods to enhance e-Macs in humans for therapeutic applications, according to Ravichandran. They have also pinpointed a subset of macrophage counterparts resembling mouse e-Macs in the pancreases of deceased human organ donors.
“Given that these waste-disposing pancreatic macrophages become protective against Type 1 diabetes, we are intrigued by the potential of harnessing their disease-preventing characteristics in individuals at high risk of this condition,” Ravichandran noted.
Future investigations aim to concentrate on increasing the proportion of e-Macs in the pancreas with the objective of aiding individuals with a family history of Type 1 diabetes to avert the disease.
Other collaborators from WashU Medicine on this research included first author Pavel Zakharov, PhD, an instructor of pathology and immunology; Xiaoxiao Wan, MD, PhD, an assistant professor of pathology and immunology; Eynav Klechevsky, PhD, an associate professor of pathology and immunology; and the late Emil R. Unanue, PhD, who passed away before witnessing the completion of the study. Unanue, a 1995 Albert Lasker Basic Medical Research Award winner, was a pioneer in elucidating the interactions between T cells and presenting cells—immune cells that showcase a sample of a potential threat on their surface—enabling T cells to identify and respond to foreign invaders.
Zakharov PN, Chowdhury CS, Peterson OJ, Barron B, Vomund AN, Gorvel L, Unanue ER, Klechevsky E, Wan X, Ravichandran KS. Efferocytic remodeling of pancreatic intra-islet macrophages by limited β-cell death. Oct. 1, 2025. Nature. DOI: 10.1038/s41586-025-09560-4
This research was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIH), grant number R01AI159551; and by the BJC Investigator Funds from WashU Medicine. The content reflects solely the authors’ viewpoints and does not necessarily represent the official perspectives of the NIH.
About Washington University School of Medicine
WashU Medicine is an international frontrunner in academic medicine, encompassing biomedical research, patient care, and educational initiatives with over 3,000 faculty members. Its National Institutes of Health (NIH) research funding portfolio ranks second largest among U.S. medical schools and has increased by 83% since 2016. Alongside institutional investments, WashU Medicine dedicates more than $1 billion annually to basic and clinical research innovations and training. Its faculty practice consistently ranks among the top five in the nation, with over 2,000 faculty physicians practicing at 130 locations. WashU Medicine doctors exclusively staff Barnes-Jewish and St. Louis Children’s hospitals—the academic facilities of BJC HealthCare — and Siteman Cancer Center, a collaboration between BJC HealthCare and WashU Medicine, and the sole National Cancer Institute-designated comprehensive cancer center in Missouri. WashU Medicine doctors also attend to patients at BJC’s community hospitals within our region. With a prestigious history in MD/PhD training, WashU Medicine recently allocated $100 million for scholarships and curriculum enhancement for its medical students, and boasts premier training programs in every medical subspecialty, alongside programs in physical therapy, occupational therapy, and audiology and communication sciences.
Originally published on the WashU Medicine website
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