A new study from Dr. Ranit Kedmi’s team at the Weizmann Institute of Science has resolved a long-standing paradox surrounding oral tolerance – the immune mechanism that helps our body recognize food as non-hostile – revealing the cellular network responsible. These findings may help researchers understand this network’s malfunctions, which underlie food allergies and sensitivities and disorders such as celiac disease.
Kedmi hypothesized that the secret to food tolerance must be sought in a type of cell she had discovered during her postdoctoral studies: ROR-gamma-t cells, whose exact lineage is still unknown. This hunch proved true. In their new Nature study, Kedmi’s team in Weizmann’s Systems Immunology Department, led by master’s student Anna Rudnitsky, showed that ROR-gamma-t, rather than conventional dendritic cells, set off the tolerance mechanism. When Rudnitsky eliminated the ability of these particular cells to present food particles to the immune system in mice, the animals rapidly developed food allergies.
In an effort to decipher the oral tolerance mechanism, the researchers managed to identify a coordinated network of four cell types crucial for preventing immune reactions to food. This network is initiated by ROR-gamma-t cells, and their signals are relayed through two other cell types to ultimately suppress the fourth: the immune system’s militant CD8 cells, normally tasked with killing infected cells or triggering inflammation against perceived threats.
The researchers then tested whether mice could develop immunity to a microbe that expresses a protein already identified by the mouse immune system as food. They revealed a remarkable dynamic: Faced with a threat, the mice’s immune systems temporarily suspended the tolerance program, deploying CD8 cells to combat the infection. Only after the infection cleared did the cellular network enable the tolerance program to resume.
In essence, Kedmi’s team has discovered a sophisticated, dynamic cellular network that allows the immune system to prevent inflammatory responses to food while simultaneously staying on guard against infection. This discovery opens promising new avenues for research into malfunctions in the oral tolerance mechanism that lead to allergies and diseases. For example, the new findings might help reveal how the final stage of the tolerance mechanism, the suppression of the CD8 cells, fails in celiac disease, causing the CD8s to mistakenly attack the intestinal lining in response to gluten. A detailed understanding of the specific points of failure within the oral tolerance network in all types of food allergies and sensitivities could pave the way for improved treatments.
