Novel Pathway for T-cell Activation in Leprosy

Dendritic cells, like scouts in the field of a military operation, deliver key information about an invading pathogen that helps activate the T-cells in launching a more effective attack. It was previously known that dendritic cells were important for a strong immune response and the number of such cells at an infection site positively correlated with a robust reaction. However, until now it was poorly understood how dendritic cells become more specialised to address specific types of infections.

The researchers found that a protein called NOD2 triggers a cell-signalling molecule called interleukin-32 that induces general immune cells called monocytes to become specialised information-carrying dendritic cells.

"This is the first time that this potent infection-fighting pathway with dendritic cells has been identified, and demonstrated to be important in fighting human disease," said the study's first author Mirjam Schenk.

In conducting the study, scientists used monocytes taken from the blood of healthy donors and leprosy patients and incubated the cells with the pathogen M. Leprae or specific parts of the mycobacteria, known to trigger NOD2 and TLR2, both associated with immune system activation.

Scientists wanted to investigate how these proteins might trigger mechanisms that turn on different immune receptors that recognize specific parts of the microbe in an infection. The NOD2 interleukin-32 pathway was the most effective and caused monocytes to develop into dendritic cells that carry critical information about the pathogen to the T-cells.

The team studied the gene expression profiles of the protein-triggered pathways and then also examined how the monocytes of leprosy patients responded to NOD2. Scientists found that NOD2 worked to induce moncytes to dendritic cells in tuberloid leprosy, a milder infection that is more easily contained. The NOD2 pathway was inhibited and could not be activated in lepromatous leprosy, which is more serious and causes widespread infection throughout the body.

"We were surprised to find the high potency of the dendritic cells in triggering certain specific T-cell responses, which may be useful in developing new therapeutic strategies for infectious diseases and cancer," said senior investigator Doctor Robert Modlin.

MEDICA.de; Source: University of California – Los Angeles