Epigenetic controls of T cells can help treat Type 1 diabetes

At St. Jude Children’s Research Hospital, researchers have generated a database that detects gene-regulatory mechanisms in immune cells that promote Type 1 diabetes. The study results were recently published in the Nature Immunology journal.

Epigenetic controls of T cells can help treat Type 1 diabetes
Senior author Ben Youngblood, Ph.D., and co-author Caitlin Zebley, MD, both of Immunology at St. Jude, discover how T cells have a dual biological personality. Image Credit: St. Jude Children’s Research Hospital.

Type 1 diabetes can be described as an autoimmune disorder in which the body’s own cells are attacked by the immune system. In this medical disorder, immune cells known as CD8 T cells destroy insulin-producing islet cells present in the pancreas.

By producing an epigenetic “atlas,” the scientists have demonstrated that such T cells exhibit a dual biological personality. It is this dual personality that allows the T cells to maintain their potential to attack insulin-producing cells over consecutive generations of T cells.

A major question has been why these T cells remain functional over long periods of time. Our research provides important insights into the stability of that response by establishing the central role of epigenetic programming in human T cell differentiation.”

Ben Youngblood, PhD, Study Senior Author, St. Jude Department of Immunology

Cellular activity is controlled by epigenetic and genetic regulation—control switches that send instructions to a cell. The mechanisms of epigenetic regulation include a process, referred to as methylation, where methyl molecules can be embedded into DNA molecules at crucial points, inhibiting their genetic activity.

Along with his research team, Youngblood plotted the pattern of methylation over the CD8 T cells’ genome to interpret the epigenetic programming that controls their “differentiation,” or development, from immature cells known as stem-memory T cells.

The scientists subsequently gathered data on methylation patterns of a wide range of T cells, spanning from naïve to active effector cells.

Based on the atlas, the scientists found that T cells responsible for causing diabetes exhibited a dual personality of naïve as well as effector-related epigenetic programs, demonstrating for the first time that these cells were epigenetic hybrids, exhibiting both programs.

Furthermore, the scientists carried out the same study on mouse CD8 T cells, demonstrating that these cells also exhibit this dual personality.

A multipotency index was crucial for interpreting both the mouse and human atlas. This multipotency index was created by the study’s co-authors Yiping Fan, Ph.D. from the St. Jude Center for Applied Bioinformatics, and also by Caitlin Zebley, MD, a clinical fellow in the Department of Immunology.

Using next-generation machine-learning approaches, both Fan and Zebley interrogated this information to decode the differentiation status of the autoreactive T cells.

Through this latest multipotency index, the team was able to demonstrate that methylation sites over the genome of T cells can be utilized to predict the differentiation of a T cell.

The auto-reactive CD8 T cells also scored high on the multipotency index, proving their conservation of the less-differentiated hybrid state.

The multipotency index and the atlas provide crucial new tools for devising diagnoses and treatments for 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.”

Ben Youngblood, PhD, Study Senior Author, St. Jude Department of Immunology

The multipotency index can potentially be utilized as the basis for a diagnostic tool to estimate the type of patients who are likely to respond to treatments that support that tolerance.

To further improve the study, Youngblood and his collaborators are partnering with the Immune Tolerance Network to assess data from previous clinical trials to check whether the multipotency index could predict the type of patients who may respond to such treatments and those who would not.

Funded by the National Institute of Allergy and Infectious Diseases, the ITN is a collaboration of scientists aiming to develop immune tolerance treatments.

Moreover, the insights gained from the epigenetic atlas can be applied to cancer immunotherapies, where T cells are designed to detect and selectively attack cancer cells.

With the help of the multipotency index, scientists could quantify the efficacy level of the engineered T cells in destroying tumor cells. The new atlas can even be used for interpreting the nature of T cell activity involved in chronic viral infections.

Source:
Journal reference:

Abdelsamed, H. A., et al. (2020) Beta cell-specific CD8+ T cells maintain stem cell memory-associated epigenetic programs during type 1 diabetes. Nature Immunology. doi.org/10.1038/s41590-020-0633-5.

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