U.S. Department of Health and Human Services

Homing in on Mechanisms to Promote Immune Tolerance—Implications for Combating Autoimmune Diseases

Researchers discovered new details of a molecular mechanism that is critical to promoting immune tolerance of the body’s own tissues, organs, and cells. In autoimmune diseases, like type 1 diabetes, the immune system launches a misguided attack against substances and tissues normally found in the body. In a person without autoimmune disease, immune cells are normally generated that recognize the body (“self”) in addition to those that recognize foreign entities such as pathogenic bacteria or virus. In a process called “tolerance,” these self-recognizing cells are muted or destroyed. Loss of tolerance, therefore, plays a role in the development of autoimmune diseases, and understanding how tolerance works and what goes wrong is critical to prevent and treat autoimmune diseases. 

Previous research shed light on this process with the discovery that a protein, called AIRE, is critical in promoting tolerance. AIRE, by turning genes on and off, generates a wide variety of “self” proteins in the thymus. The presence of these “self” proteins in the thymus promotes tolerance. However, AIRE does not generate all the “self” proteins that are present in the body, so researchers hypothesized that there must be AIRE independent mechanisms at work. To examine other potential mechanisms, scientists focused on understanding the role that a specific type of immune cell—a dendritic cell—plays in promoting tolerance. Dendritic cells can be found in immune organs like the thymus, and at interfaces between the body and the environment, like skin or the surfaces of the airway and intestine. These cells constantly “sample” the environment; they take up proteins and particulates and then “present” the sample to cells that determine whether or not to launch an immune attack. 

The researchers studied one type of dendritic cell, a plasmacytoid dendritic cell (pDC). They examined this cell type because they previously found that it contained a protein called CCR9, which is involved in homing of other immune cells to the thymus. Therefore, they speculated that CCR9 may also be involved in homing pDCs to the thymus. To test this hypothesis, they genetically engineered mice to lack the CCR9 gene and found that these mice had fewer thymic pDCs compared to normal mice, suggesting that CCR9 was important for pDC recruitment to the thymus. In addition, they intravenously injected mice with pDCs without CCR9 and observed that only a small percentage made it to the thymus. The researchers next wanted to determine whether pDCs had a role in transporting “self” proteins to the thymus. They loaded pDCs with an experimental “self” protein and injected those cells into genetically modified mice. The injected pDCs homed to the thymus and, importantly, led to the destruction of immune cells that recognized the “self” protein. Further experiments showed that pDCs within mice were able to “pick up” an experimentally introduced particulate and transport it to the thymus, a possible therapeutic approach for inducing tolerance. 

These results suggest that pDCs contribute to tolerance through CCR9-dependent transport of “self” proteins to the thymus, a process that complements AIRE-regulated mechanisms. Further research will determine whether a similar mechanism occurs in humans and whether disruption of this process is associated with type 1 diabetes and/or other autoimmune diseases. This finding could also present an exciting opportunity to identify novel approaches to promote tolerance in autoimmune diseases.

Hadeiba H, Lahl K, Edalati A, et al. Plasmacytoid dendritic cells transport peripheral antigens to the thymus to promote central tolerance. Immunity 36: 438-450, 2012.