LMU researchers have demonstrated that autoreactive T cells are activated in a specific region of the intestinal tract, and this activation is dependent on the microbiome.

Multiple sclerosis (MS) is an inflammatory autoimmune disease of the central nervous system. It is triggered by certain T cells that infiltrate the brain and spinal cord, attacking the insulating myelin sheath around axons. In recent years, researchers have found increasing evidence that the gut microbiome plays a significant role in activating these cells. However, the precise location and underlying mechanisms remained unclear. Using imaging techniques in a mouse model, a team led by Privatdozent Dr. Naoto Kawakami from the University of Munich Hospital has now successfully tracked the microbiome-dependent activation of these cells live for the first time.

The scientists conducted a study using two-photon imaging to observe how specific T cells move and become activated in real time. They used a sensor protein to track changes in cellular calcium concentration, which helped them understand the T cells’ activity. The researchers focused on encephalitogenic T cells, which can cause inflammation in the brain. These T cells target a protein in the myelin sheath around neurons and are involved in the development of multiple sclerosis.

Activation in the lamina propria

The researchers showed that the cells need to be activated in the gut-associated lymphoid tissue (GALT), located in the mucous membrane of the gut, specifically in the lamina propria, a connective tissue layer of the small intestine. However, this only occurred when the mice had a healthy intestinal microbiome. If the gut was microbe-free, activation did not happen. It is interesting to note that activation in the lamina propria appears to be a general mechanism. Even non-encephalitogenic T cells, which target other molecules in the body, showed activation depending on the microbiome. The scientists believe that the microbiome produces molecules that are recognized by the receptors in the T cells and triggers cell activation.

In encephalitogenic T cells, the activation turns on genes that cause them to differentiate into so-called Th17 cells, as the researchers successfully demonstrated. Through this differentiation, the cells develop the properties that enable them to migrate into the central nervous system and trigger inflammation. “Our results make an important contribution to better understanding the development of multiple sclerosis and potentially open up new therapy options in the long term,” says Kawakami.