For Multiple Sclerosis, First Confirmation That T Cell Activation in Gut Dependent on Microbiome

For the first time, scientists have charted the activation of gut-based T cells in multiple sclerosis using two-photon imaging in a mouse model. Further, that activation appears to be microbiome-dependent. Findings were published in Proceedings of the National Academy of Sciences.

In recent years, researchers have discovered numerous indications that the gut microbiome plays a critical role in activating certain T cells that permeate the brain and spinal cord and attack the myelin sheath that encompasses axons. The precise location and mechanisms driving this process have remained elusive until the present study led by Privatdozent Dr Naoto Kawakami, University of Munich Hospital.

"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," said Kawakami in a press release.

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Authors utilized two-photon imagining to visualize both the activation and mobility of specific engineered T cells in mice. They used a sensor protein to track changes in cellular calcium concentration, which enabled inference about the activity of the T cells that target a protein in the myelin sheath.

Myelin-targeting T cells were found to activate in gut-associated lymphoid tissue (GALT) within the ileal lamina propria (LP), a connective tissue layer in the small intestine. However, this activation only occurred in mice with an intact intestinal microbiome. Those with a microbe-free gut did not exhibit activation.

"Interestingly, activation in the lamina propria seems to be a general mechanism, as even for non-encephalitogenic T cells, which target other molecules in the body, we found that activation depended on the microbiome," Kawakami noted.

The researchers also observed the movement of T cells departing the ileal LP, migrating into the brain and spinal cord. During this transition, the activation initiates genes that cause encephalitogenic T cells to differentiate into Th17 cells, which then cause the brain inflammation associated with multiple sclerosis.

References

Bauer IJ, Fang P, Lämmle KF, et al. Visualizing the activation of encephalitogenic T cells in the ileal lamina propria by in vivo two-photon imaging. Proc Natl Acad Sci. 2023:120(30). doi.org/10.1073/pnas.2302697120

Multiple sclerosis: fateful immune cell activation in gut made visible. News release. Ludwig Maximillian University of Munich. Published online July 27, 2023. Accessed August 2, 2023.

Wexler, M. Gut bacteria may be key to activate immune cells that trigger MS. Multiple Sclerosis News Today. Published online July 28, 2023. Accessed August 2, 2023.