Autoreactive T Cells Present in Healthy Pancreas

By Will Boggs

October 29, 2020

NEW YORK (Reuters Health) - Preproinsulin-specific CD8+ T cells capable of attacking pancreatic islet cells are abundant in healthy pancreas, researchers report.

"Previous dogma said that most of these should have been edited out by the thymus or peripheral tolerance," Dr. Matthias G. von Herrath of La Jolla Institute for Immunology, in California, told Reuters Health by email.

Dr. von Herrath and colleagues earlier showed that antigen-specific CD8+ T cells recognizing preproinsulin (PPI) and other autoantigens are present in the islets of donors with recent-onset and long-standing type-1 diabetes.

In the current study, they sought to determine the exact location of such autoreactive CD8+ T cells in pancreas tissue samples from individuals diagnosed with type-1 diabetes, autoantibody-positive (at-risk) individuals and autoantibody-negative (not-at-risk) healthy controls.

The relative frequencies of PPI-specific CD8+ T cells in the exocrine regions of the pancreas were similar irrespective of disease status, suggesting that the presence of autoantigen-specific CD8+ T cells in the pancreas is the default state in humans without type-1 diabetes.

During the development of type-1 diabetes, there appears to be a progressive attraction of autoreactive T cells from the exocrine pancreas towards the islets, such that the mean frequency of PPI-specific CD8+ T cells is higher in islets from individuals with type-1 diabetes than in islets from individuals without type-1 diabetes.

The presence of insulin appears to be critical in order to attract or retain PPI-specific CD8+ T cells to the islets, the researchers report in Science Advances.

In the exocrine regions of all groups, 50% to 60% of PPI-specific CD8+ T cells were memory cells.

This "means that so called autoimmune diseases that affect a selective organ, such as type-1 diabetes or alopecia, might be caused by a local problem in this organ rather than merely systemic immune dysregulation," Dr. von Herrath said. "For example, innervation (and change thereof) could play a role; maybe local infections could play a role. These local issues appear to lead to an unmasking of the target cells (in type-1 diabetes beta cells that make insulin) to the immune system."

"The good news is that if local 'unmasking' of potential target cells of our own body can lead to such diseases, you might be able to also locally 'cloak' them and make them invisible again," he said. "This could lead to treatments that act in type-1 diabetes specifically on beta cells rather than systematically dampening the immune system."

Dr. Chikako Shimokawa of the National Institute of Infectious Diseases in Tokyo and Gunma University, in Maebashi, Japan, recently reported that CD8+ regulatory T cells are critical in the prevention of autoimmune-mediated diabetes.

"Development of type-1 diabetes might depend on 'exposure' of beta cells to preexisting autoreactive CD8 T cells rather than production of those aggressive cells," she told Reuters Health by email. "The exposure (infiltrating autoreactive T cells to islet) may be triggered by MHC class I upregulation and accumulation of PPI presumably resulting from environmental factors like viral infections and lifestyle-related diseases."

"This mechanism could not explain all type-1 diabetes etiology," Dr. Shimokawa said. "The limitation is that it applies to individuals who are able to generate PPI-specific CD8 T cells, in other words, those who have the specific HLA haplotype, HLA-A*02:01 that is able to present the PPI15-24 epitope. In fact, some donors with type-1 diabetes don't have PPI-specific CD8 T cells in this study."

SOURCE: Science Advances, online October 16, 2020.