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

SNT Gatchaman

SNT Gatchaman

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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]
 
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 [edit: an immune response] 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 [edit: is correlated with neurobehavioral changes associated with neuroimmune damage, and are well correlated with that tissue damage in other literature]

[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]
 
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Utsikt said:
Did they actually show damage here, or just the production of these?
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That's a good thing to bring up and is one of my minor quibbles with this paper. They did show a lack of tissue damage in other organs (lung spleen) and showed that there was not widespread demyelination as seen in experimental autoimmune encephalitis (EAE). The latter is because this particular TCR does not have specificity for myelin, and therefore would not be expected to show widespread inflammation detectable on a brain scan. Though they did show IBA-1+ microglial recruitment in the regions with high T-cell numbers, which is very well correlated with progressive tissue damage.

Basically, it's operating off the assumption that it would be pretty inconceivable to have no damage if you have:
1) antigen recognition in the tissue (confirmed by clonal expansion)
2) high levels of IFNg and IL-17A which are well correlated with tissue damage in both experimental autoimmune encephalitis and psoriatic lesions
3) neurobehavioral signs (e.g. ataxia) associated with progressive destruction of those tissues in other models, and
4) activated microglia in the same region as the expanded T cells

Some of the referenced studies used as justification for this one did confirm tissue damage with that exact same cytokine signature (e.g. seen in an autoimmune uveitis model here).

Long story short I would have liked to see the histology just to confirm that damage, but I can understand why they didn't feel the need to do so when all of those other signs cumulatively have proven to be pretty reliable markers of progressive tissue damage elsewhere in the literature.
 
jnmaciuch said:
That's a good thing to bring up and is one of my minor quibbles with this paper. They did show a lack of tissue damage in other organs (lung spleen) and showed that there was not widespread demyelination as seen in experimental autoimmune encephalitis (EAE). The latter is because this particular TCR does not have specificity for myelin, and therefore would not be expected to show widespread inflammation detectable on a brain scan. Though they did show IBA-1+ microglial recruitment in the regions with high T-cell numbers, which is very well correlated with progressive tissue damage.

Basically, it's operating off the assumption that it would be pretty inconceivable to have no damage if you have:
1) antigen recognition in the tissue (confirmed by clonal expansion)
2) high levels of IFNg and IL-17A which are well correlated with tissue damage in both experimental autoimmune encephalitis and psoriatic lesions
3) neurobehavioral signs (e.g. ataxia) associated with progressive destruction of those tissues in other models, and
4) activated microglia in the same region as the expanded T cells

Some of the referenced studies used as justification for this one did confirm tissue damage with that exact same cytokine signature (e.g. seen in an autoimmune uveitis model here).

Long story short I would have liked to see the histology just to confirm that damage, but I can understand why they didn't feel the need to do so when all of those other signs cumulatively have proven to be pretty reliable markers of progressive tissue damage elsewhere in the literature.
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I’m mostly asking because their title says «gut inflammation» when talking about what I assume is just the presence of cytokines. That would be a bit like saying that there is a «shed fire» because it’s filled with firewood. And that there now is a «house fire» because I brought some firewood into the house.

And can’t e.g. ataxia be caused by loads of other issues other than «neuroinflammation»?

It just seems weird to not check for the damage, even if you might be fairly certain that it is there.
 
Utsikt said:
I’m mostly asking because their title says «gut inflammation» when talking about what I assume is just the presence of cytokines.
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They did actually show histology of gut tissues, though I only have an amateur eye for analyzing that.

Utsikt said:
And can’t e.g. ataxia be caused by loads of other issues other than «neuroinflammation»?

It just seems weird to not check for the damage, even if you might be fairly certain that it is there.
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Ataxia can definitely be caused by other things. They do have good evidence of immune cell infiltration, which is one of the things you look for to confirm inflammation, but they don't show changes in tissue architecture. It is possible that because the T cells used for transfer only targeted specific CNS proteins, they would not have produced visually obvious signs of tissue architecture changes anyways--that's more a guess on my part though, it's outside of my realm of expertise.

Like I said, none of the pieces of evidence individually would prove inflammation, but cumulatively its pretty hard to believe that all this can occur and not result in tissue damage. They also had several side experiments showing e.g. if you block activation of microglia or one of those specific cytokines, you don't get the neurobehavioral phenotypes. So overall I think there's good evidence of causal association between all the puzzle pieces justifying their claim of neuroinflammation even if they didn't specifically show altered tissue architecture.

[edit: I've updated some of my earlier posts to avoid confusion on what exactly the paper shows]
 
Since there is no evidence for a disease in humans involving that contrived in the mouse I see this as completely irrelevant and distasteful (subjecting animals to pain for no good reason).
 
From the extended discussion:
Despite the positive clinical impact of the advent of ICB in a range of cancer types, in a key trial, 68.7% of patients administered ICB developed treatment-induced immune-related adverse events (irAEs) characterized by the autoimmune-like inflammation of several organs6. Neurological irAEs such as hypophysitis develop in ~14% of patients after anti-CTLA4 and PD-1 therapy7. Although the causes of these irAEs are not understood, commensals are likely to play a role in this process given that they are highly associated with many autoimmune diseases. It is thus possible that patients with irAEs harbor commensal-specific T cells that are also cross-reactive to host proteins, with these cross-reactive T cells becoming further dysregulated in response to ICB.

Consistent with such a model, gut T cells have previously been shown to contribute to the incidence of CNS inflammation in the context of celiac disease and IBD8,9. While celiac disease is caused by the generation of food-reactive T cells and other immune populations with affected patients experiencing abdominal pain in the small intestine where food-derived antigens are abundant, a subset of celiac disease patients also exhibit inflammation in the brain10,11, presumably due to the migration of dysregulated T cells from the gut to the CNS. Gut inflammation in IBD patients and mouse models is highly associated with various neurological disorders 12,13. Our animal model can thus serve as an effective tool for studies of commensal-derived neurological irAEs and extraintestinal manifestations of IBD and celiac disease, which are common in human patients yet lack ideal animal models for research use. On the other hand, tumor neoantigens could similarly be targeted by microbiota-specific T cells to help the anti-tumor response 14. Understanding the extraintestinal roles of gut commensal-specific T cells and their utilization would be an attractive anti-tumor therapy.
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I don't think they are saying that, given that the point of the paper was microbiota-specific molecular mimicry. They should have clarified to avoid misunderstanding, perhaps.

The second paragraph seems to be additional speculation, whereas the first issue (neurological autoimmunity during immune checkpoint blockage) was explicitly mentioned as justification for the study in the results of the main paper.
 
jnmaciuch said:
I don't think they are saying that, given that the point of the paper was microbiota-specific molecular mimicry. They should have clarified to avoid misunderstanding, perhaps.

The second paragraph seems to be additional speculation, whereas the first issue (neurological autoimmunity during immune checkpoint blockage) was explicitly mentioned as justification for the study in the results of the main paper.
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I was only being frivolous, but where does molecular mimicry come in to Coeliac disease, pray? And where is this imaginary brain pathology? The misunderstanding is all theirs. It has been going on for sixty years now and it has no more relation to reality than the Wizard of Oz.
 
Jonathan Edwards said:
I was only being frivolous, but where does molecular mimicry come in to Coeliac disease, pray? And where is this imaginary brain pathology? The misunderstanding is all theirs. It has been going on for sixty years now and it has no more relation to reality than the Wizard of Oz.
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Again, it's only briefly conjecturing about the possibility of involvement in celiac and IBD having proven that microbe-specific T cells are capable of inducing CNS inflammation here. It does not claim that this necessarily is the case in celiac. The main justification for this study is evidence of neurological autoimmunity in ICB use.
 
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