Tuning of human MAIT cell activation by commensal bacteria species and MR1-dependent T-cell presentation, 2018, Unutmaz et al

[Andy]

Abstract

Human mucosal-associated invariant T (MAIT) cell receptors (TCRs) recognize bacterial riboflavin pathway metabolites through the MHC class 1-related molecule MR1. However, it is unclear whether MAIT cells discriminate between many species of the human microbiota. To address this, we developed an in vitro functional assay through human T cells engineered for MAIT-TCRs (eMAIT-TCRs) stimulated by MR1-expressing antigen-presenting cells (APCs). We then screened 47 microbiota-associated bacterial species from different phyla for their eMAIT-TCR stimulatory capacities. Only bacterial species that encoded the riboflavin pathway were stimulatory for MAIT-TCRs. Most species that were high stimulators belonged to Bacteroidetes and Proteobacteria phyla, whereas low/non-stimulator species were primarily Actinobacteria or Firmicutes. Activation of MAIT cells by high- vs low-stimulating bacteria also correlated with the level of riboflavin they secreted or after bacterial infection of macrophages.

Remarkably, we found that human T-cell subsets can also present riboflavin metabolites to MAIT cells in a MR1-restricted fashion. This T–T cell-mediated signaling also induced IFNγ, TNF and granzyme B from MAIT cells, albeit at lower level than professional APC. These findings suggest that MAIT cells can discriminate and categorize complex human microbiota through computation of TCR signals depending on antigen load and presenting cells, and fine-tune their functional responses.

Paywalled at https://www.nature.com/articles/s41385-018-0072-x

While this is in "Unrelated to ME/CFS research" forum, the blog below, from Jackson Labs, suggests that it could have some implication in ME.

Jackson Labs ME/CFS Collaborative Center Director Derya Unutmaz and his collaborator and microbiome expert Julia Oh recently published a study in the journal Mucosal Immunology, titled “Tuning of human MAIT cell activation by commensal bacteria species and MR1-dependent T-cell presentation.” Mucosal-associated invariant T (MAIT) cells are a type of T cell present in various sites of the body, including the gut mucosa, and defend against microbial infection by recognizing a particular bacterial metabolite shown to them by antigen presenting cells (APCs). In the gut microbiota, there are many different species of bacteria present and yet, MAIT cells don’t mount an immune response to all of them. It is therefore likely that these cells can distinguish which types of bacteria are beneficial to us and which are harmful. The findings from this study could be highly relevant for ME/CFS patients, who are thought to have disruptions of both their immune system and their microbiome.

https://jaxmecfs.com/2018/09/24/750/

 

[FMMM1]

Check out Fluge an Mella's (December 2016) paper "Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/chronic fatigue syndrome" [https://insight.jci.org/articles/view/89376]. The authors state "According to this model, ME/CFS is caused by immune interference with an unidentified target, potentially a signaling factor, which ultimately causes metabolic dysfunction and induction of secondary rescue mechanisms".
So possibly this paper by "Derya Unutmaz and his collaborator and microbiome expert Julia Oh" [https://jaxmecfs.com/2018/09/24/750/] helps fills in a bit of the mechanism. Basically MAIT cells, in your gut lining, are activated by a change in the composition of your microbiome (gut bugs) i.e. increased Bacteroidetes to Firmicutes ratio. The immune activation [i.e. of MAIT cells] is the source of the change in cellular energy production in ME/CFS.

Here's an extract from Unutmaz/Oh's paper "This T–T cell-mediated signaling also induced IFNγ, TNF and granzyme B from MAIT cells, albeit at lower level than professional APC [antigen presenting cells]" [https://www.nature.com/articles/s41385-018-0072-x]. Are "IFNγ, TNF and granzyme B from MAIT cells" the "signaling factor" that Fluge an Mella propose?

Note that Fluge and Mella found that tryptophan levels in blood were low i.e. because it was being use for cellular energy production. Robert Phair/Ron Davis found that intracellular levels of tryptophan were high. We don't have all of the information but possibly Unutmaz/Oh's, and Phair/Davis's, will come together i.e. once we have more information e.g. the signalling factor which causes the change in the cellular energy production.

I've missed out Chris Armstrong's work, he first identified the switch to using proteins for cellular energy production and then proposed that the change in the energy production caused the change in the microbiome creating ME/CFS [2016 Webinar]. Chris proposed that there was a (negative) cycle maintaining a stable disease state i.e. change in energy production maintained the pathogenic microbiome -- pathogenic microbiome maintained the change in energy production ---. Robert Phair refers to bistability.



Please think about lobbying for more funding from the European Union.Lyme disease got 33.9 million (dollars/euros) from the European Union Horizon 2020 (science and technology) fund; ME/CFS got zero.

Here's a draft letter I'm hoping to send to Members of the European Parliament (MEPs) seeking support for research/development of a diagnostic test for ME/CFS. If you can lobby MEPs, or know others who can (e.g. those involved in the missing million campaign throughout Europe), then I'd be grateful for your assistance.

*Draft letter to MEPs:
"Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) affects more than one million people within the EU. This illness is characterised by persistent and excessive fatigue, post-exertional malaise, flu-like symptoms and cognitive impairments. Most sufferers are unable to lead a normal life. Those affected are predominately women. Many people with ME/CFS feel that they are labelled as having a psychological condition and that research into ME/CFS is not prioritised as a result of this "psychological" label.

Many of the symptoms of ME/CFS overlap with those of Lyme disease and fibromyalgia.

There are no established biological diagnostic tests for ME/CFS, nor are there any treatments.

Professor Carmen Scheibenbogen, Charite, Germany recently discovered that people with ME/CFS can be separated from healthy people by measuring the expression of three genes.
Professor Julia Newton at Newcastle University found that differences in cellular energy production can be used to separate people with ME/CFS from healthy people.
These discoveries could be the basis of a biological diagnostic test for ME/CFS.

There are other excellent researchers in the European Union working on ME/CFS e.g. Professor Jonas Bergquist Uppsala University, Sweden; Professor Øystein Fluge and Olav Mella Haukeland universitetssykehus Norway.

The European Commission has funded the European Network on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome [EUROMENE] under the Cooperation in Science and Technology (COST) program. However, the Commission, in its response to a Parliamentary Question on Funding of research on ME/CFS [E-006901/2017] acknowledge that it had not funded any research into ME/CFS:
"To date, no specific projects on ME/CFS have been supported by the EU Framework Programmes for Research and Innovation."

Request:
I would be grateful if you would lobby the European Commission to ask that they fund research into ME/CFS, including the development of a diagnostic test. ME/CFS affects approximately 1 million people in the European Union; most of them are unable to lead a normal life. The development of a diagnostic test, and effective treatments, would help to reduce the suffering of these people."

 

[Andy]

Interesting post @FMMM1 . To get the most response to your request for lobbying of MEPs, I'd suggest creating a new thread for it, as this will increase the number of people who see it.

 

[Andy]

Also tagging @Amy Proal , who is probably aware of this paper but doing so just in case.

 

[FMMM1]

Interesting post @FMMM1 . To get the most response to your request for lobbying of MEPs, I'd suggest creating a new thread for it, as this will increase the number of people who see it.

Thanks for your reply. I should have added a few caveats to my post; there's a lot of jumping between widely separated known pieces of this jigsaw.

I don't know how to create a separate thread regarding lobbying; however, I' be grateful for advice/assistance.

 

[Trish]

I don't know how to create a separate thread regarding lobbying...

I'll send you a private message to explain. Look at your inbox.

 

[Hoopoe]

Here's an extract from Unutmaz/Oh's paper "This T–T cell-mediated signaling also induced IFNγ, TNF and granzyme B from MAIT cells, albeit at lower level than professional APC [antigen presenting cells]" [https://www.nature.com/articles/s41385-018-0072-x]. Are "IFNγ, TNF and granzyme B from MAIT cells" the "signaling factor" that Fluge an Mella propose?

Whatever it is that affects cells, it doesn't seem to lose its effect as time goes on. All the three reseacher groups have shown effects that persist for hours or even days.

I vaguely remember discussions on cytokine tests being potentially unreliable because cytokines are so unstable. Maybe @Jonathan Edwards can say more?

 

[FMMM1]

Whatever it is that affects cells, it doesn't seem to lose its effect as time goes on. All the three reseacher groups have shown effects that persist for hours or even days.

I vaguely remember discussions on cytokine tests being potentially unreliable because cytokines are so unstable. Maybe @Jonathan Edwards can say more?

View attachment 5272

Thanks

I think Ron Tompkins (spelling?) OMF pointed out that the expected cytokine storm in SEPSIS didn't occur/exist. I.e. cytokine levels weren't that high in SEPSIS - same goes for ME/CFS. Cort Johnson's article (see link above - in my original post) mentions this i.e. cytokines don't drive the disease process in SEPSIS (ME/CFS?). So folks like Mandy Hornig (2015 paper?) really had to control their sampling etc. re cytokines to pick up the underlying inflammation in ME/CFS. We need someone like @Jonathan Edwards [don't think that tag worked] to comment on the significance or otherwise of this [Unutmaz/Oh's] paper.

Here's a web address I've been sent i.e. for the full paper - https://sci-hub.se/10.1038/s41385-018-0072-x