How NKT Cells See “Self” Shapes Inflammatory Response

Research identifies transcription factor involved in triggering or tampering defense.

Recent discoveries published in the Proceedings of the National Academy of Sciences reveal that a transcription factor, Nur77, is part of a control mechanism that ensures natural killer T (NKT) cells do not become hyperactive and cause autoimmune or autoinflammatory diseases.

NKT cells are white blood cells that help the body defend against infection and maintain homeostasis. This defense mechanism should be optimal, as an unbridled NKT cell-mediated response can cause inflammatory disease.

“NKT cells can be involved in protecting the host, but they can also go rogue and precipitate inflammatory diseases,” said senior author Sebastian Joyce, Ph.D., Dorothy B. and Theodore R. Austin Chair in pathology at Vanderbilt University Medical Center.

“NKT cells can be involved in protecting the host, but they can also go rogue and precipitate inflammatory diseases.”

“The data presented … are an important advance in understanding the molecular mechanisms controlling NKT cells,” said Leslie Crofford, M.D., director of the Division of Rheumatology and Immunology at Vanderbilt. “Targeting these mechanisms could provide a novel strategy for intervention in people with autoimmune or autoinflammatory diseases.”

Natural Killer T Cells

NKT cells have characteristics of both the innate and adaptive immune systems. A hallmark of their activation is the rapid and robust production of soluble mediators such as cytokines and chemokines.

“Unlike conventional T cells that take time to get activated, NKT cells come loaded and ready to respond to any sight of altered homeostasis,” said Amrendra Kumar, Ph.D., first author on the study and a research instructor in the Department of Pathology, Microbiology and Immunology at Vanderbilt.

Normally, NKT cells help to suppress the formation of autoimmune diseases. “Hence, you can harness the activity of NKT cells to prevent, for example, the formation of type 1 diabetes in mice,” Joyce said. This disease-suppressing NKT cell function was discovered by study coauthor, Luc Van Kaer, Ph.D., Elizabeth and John Shapiro Chair of the Vanderbilt Institute for Infection, Immunology and Inflammation.

“The question is, how do NKT cells recognize self only to an extent where they maintain tolerance but not become autoreactive and cause disease?”

If turned on in the wrong context, NKT cells can cause autoimmunity and other inflammatory diseases. For example, hyperactivated NKT cells have been shown to precipitate arthrosclerosis.

Joyce explained that to function, NKT cells recognize “self,” or the body’s own agonistic molecules. “The question is, how do NKT cells recognize self only to an extent where they maintain tolerance but not become autoreactive and cause disease?” he said.

 

The Role of Nur77

In the new study, the researchers discovered that Nur77 – a transcription factor expressed at high levels in NKT cells – plays a central role in self-tolerance induction of NKT cells.

Overexpression of Nur77 in mice was found to induce apoptosis and T cell exhaustion in NKT cell precursors, hindering the development of NKT cells. The study also found that overexpression of Nur77 caused NKT cells to be hyporesponsive to a high-affinity agonist.

“This helps explain how NKT cells attain tolerance to self,” Joyce said. “Through the function of Nur77, NKT cells themselves can control cell differentiation, cell tolerance induction and effector function.”

The research team is eager to pin down the cell intrinsic and extrinsic factors that regulate Nur77 expression and function. “Understanding the mechanisms of self-tolerance in this lineage is of immunologic import, because NKT cells are self-reactive and mediate microbial and sterile inflammation,” they wrote.