Immunologists at St. Jude Children's Research Hospital have created a database that identifies gene-regulatory mechanisms in immune cells that facilitate Type 1 diabetes. The findings were published today in Nature Immunology.
Type 1 diabetes is an autoimmune disease in which the immune system attacks the body's own cells. In Type 1 diabetes, immune cells called CD8 T cells kill insulin-producing islet cells in the pancreas. By creating an epigenetic "atlas," the researchers revealed that these T cells have a dual biological personality. That dual personality enables the T cells to retain the ability to attack insulin-producing cells across successive generations of T cells.
"A major question has been why these T cells remain functional over long periods of time," said senior author Ben Youngblood, Ph.D., of the St. Jude Department of Immunology. "Our research provides important insights into the stability of that response by establishing the central role of epigenetic programming in human T cell differentiation."
Regulation through epigenetics
The activity of cells is governed by genetic and epigenetic regulation, control switches that give instructions to a cell. The epigenetic regulation mechanisms include a process called methylation in which methyl molecules can be plugged into DNA molecules at key points to suppress their genetic activity.
Youngblood and his team charted the pattern of methylation across the genome of CD8 T cells to understand the epigenetic programming that governs their development, or "differentiation," from immature cells called stem-memory T cells. The researchers collected data on methylation patterns of a variety of T cells, ranging from naïve-- not yet possessing the ability to attack -- to active effector cells.
From the atlas, investigators discovered that the diabetes-causing T cells possessed a dual personality of both naïve and effector-associated epigenetic programs, revealing for the first time that the cells were epigenetic hybrids, possessing both programs.
The researchers also performed the same analysis on mouse CD8 T cells, revealing they also showed such a dual personality.
Understanding a dual personality
A key to understanding both the human and mouse atlas was a multipotency index developed by co-authors Yiping Fan, Ph.D., of the St. Jude Center for Applied Bioinformatics, and Caitlin Zebley, M.D., a clinical fellow in the Department of Immunology. Through cutting-edge, machine-learning approaches, Fan and Zebley interrogated this data to understand the differentiation status of the autoreactive T cells. Using this novel index, they were able show that methylation sites across the T cells' genome can be used to predict a T cell's differentiation.
The autoreactive CD8 T cells scored high on the index, revealing their preservation of the less-differentiated hybrid state. The atlas and the multipotency index offer important new tools for developing treatments and diagnosis of Type 1 diabetes.
"We now have an epigenetic signature for these cells that we can use to explore treatments for Type 1 diabetes that induce immunological tolerance of these T cells to prevent their attack on islet cells," Youngblood said.
The index could be used as the basis for a diagnostic tool to predict which patients would respond to therapies that encourage that tolerance. To advance this work, Youngblood and his colleagues are collaborating with the Immune Tolerance Network to examine data from past clinical trials to see whether the index could predict which patients would respond to such therapies and which would not. The ITN, funded by the National Institute of Allergy and Infectious Diseases, is a collaboration of researchers aimed at developing immune tolerance therapies.
The insights from the epigenetic atlas can also be applied to cancer immunotherapies, in which T cells are engineered to recognize and selectively attack tumor cells. Using the multipotency index, researchers could measure how effective such engineered T cells would be in attacking cancer cells. The atlas can also be used to understand the nature of T cell activity in chronic viral infections.
Co-first authors on the paper are Hossam Abdelsamed, formerly of St. Jude and now of the University of Pittsburgh School of Medicine; Caitlin Zebley of St. Jude; and Hai Nguyen of the Benaroya Research Institute. Other authors include Hazem Ghoneim, Jeremy Crawford, Ashley Castellaw, Maureen McGargill, Shanta Alli, Shannon Boi and Hongjian Jin all of St. Jude; Eddie James, Gerald Nepom and Cate Speake of the Benaroya Research Institute; Rachel Rutishauser and Steven Deeks of the University of California, San Francisco; Francesca Alfei and Dietmar Zehn of the Technical University of Munich; Susan Pereira Ribeiro and Rafick-Pierre Sekaly of Case Western Reserve University; Elisavet Serti of the Immune Tolerance Network; Laurence Turka of Massachusetts General Hospital and Harvard Medical School and Michael Busch and Mars Stone of the Vitalant Research Institute.
This research was supported by the National Institutes of Health (1R01AI114442), the Immune Tolerance Network (UM1AI109565), the Assisi foundation and ALSAC, the fundraising and awareness organization of St. Jude.
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