Nature Reviews Immunology, Published online: 24 June 2025; doi:10.1038/s41577-025-01201-1

White et al. show that microbiota-specific T cells are licensed by gut inflammation to infiltrate the central nervous system, where cross-reactivity with self-antigens leads to neuropathology.



Summary

A research article published in Nature Reviews Immunology by White et al. on June 24, 2025, investigates the intricate relationship between the gut microbiota, T cell responses, and the development of neuropathology. The study reveals a critical mechanism by which microbiota-specific T cells, under specific inflammatory conditions within the gut, gain the ability to infiltrate the central nervous system (CNS). Once within the CNS, these T cells can cross-react with self-antigens, triggering an autoimmune response that ultimately leads to neurological damage.

The core finding of the study highlights that gut inflammation acts as a “license” for microbiota-specific T cells to migrate beyond the gut and penetrate the highly regulated CNS. This licensing process involves alterations in the T cells’ characteristics, allowing them to overcome the stringent blood-brain barrier that normally prevents immune cells from entering the CNS.

Normally, the CNS enjoys a degree of immune privilege, maintained by the blood-brain barrier and other mechanisms. These systems restrict the entry of immune cells and limit inflammatory responses within the brain and spinal cord, protecting these delicate tissues from immune-mediated damage. However, in certain circumstances, this immune privilege can be compromised, leading to neuroinflammation and the development of autoimmune neurological disorders.

White et al.’s research suggests that gut inflammation can be a crucial trigger for breaking down this immune privilege. They propose that the inflammatory environment in the gut alters the expression of adhesion molecules and chemokine receptors on the surface of microbiota-specific T cells. This modification allows these T cells to bind to and migrate across the blood-brain barrier.

Crucially, the study emphasizes the role of cross-reactivity in the development of neuropathology. Once within the CNS, these microbiota-specific T cells encounter self-antigens that bear structural similarities to the microbial antigens they were originally trained to recognize. This phenomenon, known as molecular mimicry, can lead to the activation of these T cells by self-antigens.

The activation of these autoreactive T cells within the CNS triggers a cascade of inflammatory events. These events include the release of pro-inflammatory cytokines, the recruitment of other immune cells, and the direct attack on neuronal and glial cells. Over time, this chronic inflammation leads to significant damage to the neural tissue, resulting in various neurological symptoms and pathologies.

The findings of White et al. have significant implications for understanding the pathogenesis of autoimmune neurological disorders such as multiple sclerosis (MS), autoimmune encephalitis, and other conditions where the immune system attacks the CNS. The study suggests that dysbiosis in the gut microbiota and associated gut inflammation could play a pivotal role in initiating or exacerbating these diseases.

Moreover, the research provides a potential therapeutic target for these conditions. Modulating the gut microbiota, reducing gut inflammation, or specifically targeting the microbiota-specific T cells that infiltrate the CNS could potentially prevent or alleviate the neuropathology associated with these disorders. For instance, strategies aimed at restoring a healthy gut microbiota composition, such as fecal microbiota transplantation or dietary interventions, might help to dampen the inflammatory response in the gut and reduce the licensing of T cells for CNS infiltration.

In conclusion, White et al.’s research provides a compelling mechanistic link between the gut microbiota, gut inflammation, and the development of neuropathology. The study highlights the crucial role of microbiota-specific T cells that are licensed by gut inflammation to cross the blood-brain barrier and initiate autoimmune responses within the CNS. These findings offer valuable insights into the pathogenesis of autoimmune neurological disorders and provide potential avenues for developing novel therapeutic interventions aimed at modulating the gut microbiota and the associated immune responses to prevent or treat these debilitating conditions.

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