A Pathway To Blocking Autoimmunity

Natural killer T (NKT) cells maintain the immune system's balance between destruction and tolerance, a mechanism that is off kilter in autoimmune diseases such as type 1 diabetes and irritable bowel disease.

“If we can regulate the level of NKT cells, we have a chance to slow down the process of type 1 diabetes,” said team leader László Nagy, HHMI international research scholar and a molecular biologist at the Research Center for Molecular Medicine, University of Debrecen, Hungary. He and colleagues from the Research Center collaborated with a scientist from Albert Einstein College of Medicine in New York to do the series of experiments, which was published in the July 2004 issue of the journal Immunity.

After finding that a transcription factor called PPAR-gamma is expressed in dendritic cells—the immune system's first responders—Nagy and colleagues used a drug called rosiglitazone to increase PPAR-gamma activity. The additional PPAR-gamma activity prompted immature dendritic cells to develop into a form that could activate NKT cells specifically.

“Everyone knew that dendritic cells are derived from monocytes, and we knew there were different kinds of dendritic cells,” Nagy said. “But nobody knew the regulatory events that drove dendritic cells to differentiation. We described a pathway to make dendritic cells with a special phenotype that includes NKT cell induction.”

Dendritic cells wait in peripheral tissue, such as the skin, ready to engulf foreign invaders or dying cells. Once they take up fragments of these cells, known as antigens, they migrate to the lymph nodes, where they prime T cells to mount a specific immune response against that antigen. The type of immune response induced varies depending on the form of dendritic cells.

Nagy believes his group has found a way to make dendritic cells that favor recognition and tolerance of self - preventing, for example, the destruction of the insulin-producing beta cells of the pancreas that occurs in type 1 diabetes.

Once they found that PPAR-gamma was expressed in dendritic cells, the researchers profiled each gene regulated by PPAR-gamma to characterize the pathway leading to NKT activation. They were able to show that PPAR-gamma regulated the expression of a gene called CD1d, which encodes a glycoprotein responsible for the presentation of self and foreign lipids to T cells. This protein is indispensable for the generation of NKT cells.

The researchers state that the work provides insight into how signals from outside the cell can influence differentiation and gene expression and is an entry point for intervention into autoimmunity by modulating CD1d expression, and NKT cell activation.

“We think PPAR-gamma is capable of orchestrating a coordinated response whether endogenous ligands arrive from outside of the cell or are generated inside the cell,” Nagy said.

Previous studies with non-obese diabetic (NOD) mice, a model of type 1 diabetes, support the idea that modulating NKT cell levels can help combat autoimmunity. These studies have linked the process of beta-cell destruction and development of type 1 diabetes to the CD1d gene and NKT cells. In 2003, another research group reported that treating NOD mice with a molecule that activates PPAR-gamma substantially reduced development of type 1 diabetes.

Although the current studies were limited to cultured human cell lines, Nagy sees potential for testing the mechanism in patients. Rosiglitazone, the drug they used to activate PPAR-gamma, is already used in the United States to improve insulin sensitivity in patients with type 2 diabetes. Nagy suggested that looking for changes in the NKT cells of patients taking rosiglitazone would indicate whether the mechanism is active.

Nagy and colleagues continue to study the PPAR-gamma pathway, and have recently begun using mouse models to knock out relevant components—PPAR-gamma, CD1d, and NKT cells—to evaluate their impact on the pathway's function.