Gut inflammation promotes microbiota-specific CD4 T cell-mediated neuroinflammation, 2025, White et al.

[SNT Gatchaman]

Gut inflammation promotes microbiota-specific CD4 T cell-mediated neuroinflammation
White, Zachary; Cabrera, Ivan; Mei, Linghan; Clevenger, Margarette; Ochoa-Raya, Andrea; Kapustka, Isabel; Dominguez, Joseph R.; Zhou, Jinyan; Koster, Kevin P.; Anwar, Shehata; Wang, Qianxun; Ng, Charles; Sagoshi, Shoko; Matsuo, Takashi; Jayawardena, Dulari; Kim, Seung Hyeon; Kageyama, Takahiro; Mitchell, Benjamin J.; Rivera, Dante; Dudeja, Pradeep K.; Lutz, Sarah E.; Kim, Ki-Wook; Yoshii, Akira; Chevrier, Nicolas; Inoue, Makoto; Sano, Teruyuki

The microbiota has been recognized as a critical contributor to various diseases1, with multiple reports of changes in the composition of the gut microbiome in contexts such as inflammatory bowel disease2,3 and neurodegenerative diseases4. These microbial shifts can exert systemic effects by altering the release of specific metabolites into the bloodstream5,6, and the gastrointestinal microbiota has also been reported to exhibit immunomodulatory activity through the activation of innate and adaptive immunity7,8. However, it remains unclear how the microbiota contributes to inflammation in the central nervous system (CNS), where these microorganisms are typically absent.

Here we report that T cells that recognize gut-colonizing segmented filamentous bacteria can induce inflammation in the mouse intestine and CNS in the absence of functional regulatory T cells. Gut commensal-specific CD4 T cells (Tcomm cells) that are dysregulated in the inflamed gut can become licensed to infiltrate into the CNS regardless of their antigen specificity and have the potential to be re-stimulated by host protein-derived antigens in the CNS via molecular mimicry, whereupon they produce high levels of GM-CSF, IFNγ and IL-17A, triggering neurological damage. These infiltrated Tcomm cells initiate CNS inflammation by activating microglia through their IL-23R-dependent encephalitogenic programme and their IL-23R-independent GM-CSF production.

Together, our findings reveal potential mechanisms whereby perturbation of Tcomm cells can contribute to extraintestinal inflammation.

Link | PDF (Nature) [Paywall]

 

[SNT Gatchaman]

(In mice)

 

[jnmaciuch]

I quite like this paper. So far I don’t have any major methodological complaints. I’m usually quite skeptical of molecular mimicry theories but this evidence seems to be as straightforward as it gets.

[Explain like I’m brain-foggy]:
This study found evidence that T cells in mice primed to recognize a certain bacterial strain from the gut are also capable of inducing an autoimmune response against the central nervous system. This is due to similarly in the amino acid sequence between the bacterial antigen and certain neuronal proteins (i.e. molecular mimicry)

Although the affinity of these T cells is very weak for central nervous system (CNS) proteins, it is enough to cause damage so long as they can bypass the suppressive effect of regulatory T cells. The authors speculate that the weak affinity for CNS proteins is what allows these T cells to bypass initial negative selection—a developmental stage where T cells are screened for reactivity to self-antigens and eliminated if they are too autoreactive.

This study indicates that these autoreactive T cells are present in healthy cases as well, but are just adequately suppressed by Tregs after passing negative selection so they do not normally cause autoimmune damage.

Once “reactivated” in the CNS, these T cells express high levels of certain cytokines, which ultimately manifests in profound tissue damage and neurological symptoms.

[Edit: the proof of this study primarily comes from taking only T cells that react to one specific bacterium and transplanting them into a mouse that is incapable of creating its own mature T and B cells]