Mitochondrial complex III is essential for suppressive function of regulatory T cells.

[Murph]

Mitochondrial complex III is essential for suppressive function of regulatory T cells.
Weinberg SE1, Singer BD1,2, Steinert EM1, Martinez CA2, Mehta MM1, Martínez-Reyes I1, Gao P3, Helmin KA1, Abdala-Valencia H1, Sena LA1, Schumacker PT4, Turka LA5, Chandel NS6.
Author information
1
Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
2
Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
3
Robert H. Lurie Cancer Center Metabolomics Core, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
4
Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
5
Rheos Medicines, Cambridge, MA, USA.
6
Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. nav@northwestern.edu.
Abstract
Regulatory T cells (Treg cells), a distinct subset of CD4+ T cells, are necessary for the maintenance of immune self-tolerance and homeostasis1,2. Recent studies have demonstrated that Treg cells exhibit a unique metabolic profile, characterized by an increase in mitochondrial metabolism relative to other CD4+ effector subsets3,4. Furthermore, the Treg cell lineage-defining transcription factor, Foxp3, has been shown to promote respiration5,6; however, it remains unknown whether the mitochondrial respiratory chain is required for the T cell-suppression capacity, stability and survival of Treg cells. Here we report that Treg cell-specific ablation of mitochondrial respiratory chain complex III in mice results in the development of fatal inflammatory disease early in life, without affecting Treg cell number. Mice that lack mitochondrial complex III specifically in Treg cells displayed a loss of T cell-suppression capacity without altering Treg cell proliferation and survival. Treg cells deficient in complex III showed decreased expression of genes associated with Treg function, whereas Foxp3 expression remained stable. Loss of complex III in Treg cells increased DNA methylation as well as the metabolites 2-hydroxyglutarate (2-HG) and succinate that inhibit the ten-eleven translocation (TET) family of DNA demethylases7. Thus, Treg cells require mitochondrial complex III to maintain immune regulatory gene expression and suppressive function.

PMID:
30626970
DOI:
10.1038/s41586-018-0846-z
https://www.ncbi.nlm.nih.gov/pubmed/30626970

 

[Murph]

I don't pretend to fully understand the relevance of this to us.

But the research on our T reg cells suggests that their number and function is important. And this paper is in Nature so the finding is apparently a big deal.

 

[bertiedog]

I don't pretend to fully understand the relevance of this to us.

But the research on our T reg cells suggests that their number and function is important. And this paper is in Nature so the finding is apparently a big deal.

I am not sure if the following helps but thought it was worth copying here. It's from Examine.com and it is referring to Reishi (Ganoderma) which I have just started to take -

"T cells
Promotion of naive CD4+ T-cells into effector T-cells occurs under the influence of cytokines. There are four types of T-cell types; Th1, Th2, Th17, and Treg[131] and all are intimiately involved with the aforementioned dendritic (antigen-presenting protein, or APN) cells. Interestingly, Ganoderma beta-glucans can increase proliferation of immature CD4+ T-cells just as potently as LPS, a pro-inflammatory molecule.[127]

Ganoderma has been implicated in increase Th1 differentiation. Additionally, the third subset of T-cells (Th17) seems to be preferentially increased after polysaccharide ingestion without inflammatory stimuli via increasing IL-23p19 secretion by dendritic cells.[127] Conversely, incubation with LPS to induce pro-inflammatory signalling suppressed IL-23p19 production and favored IL-12p40 production, which was barely existent without LPS.[127] The increase in IL-23p19 production is mediated by beta-glucans in Ganoderma (and has been reported elsewhere[132]) and is via the ERK/MEK pathway; all the above effects have been seen in vivo after oral ingestion.[127]

An increase in Treg cell (Foxp3+; a major class of T regulatory cells[133]) has been noted with the LZ-8 protein in Reishi, where 1μg/mL applied to CD4+ cells increased Treg expression 4 to 10-fold resulting in increased IL-2 and IL-10 secretion;[103] implanting these activated Treg cells into mice with intestinal inflammation show suppressive effects (seen with other Treg cell inducers such as lactobacillus reuteri).[103]

The stimulatory effect of Reishi appears to extend to T cells
There is a method of training for athletes known as "living high and training low" which involves training at or near sea level and training at a higher altitude, thought to achieve the benefits of hypoxic training[134] although it is associated with immunosuppression (related to NK cells and T cells).[135]

In football players subject to a hypoxic sleep condition (mimicking 2500m altitude) and training in normoxic conditions Reishi supplementation at 2.5-5g (water soluble polysaccharide extract) for 28 days noted that while the short-term immunosuppression (assessed by CD3+, CD4+, and CD8+ T-cell counts) was attenuated in control the CD3+ T-cells with 5g Reishi were stimulated past control and placebo levels.[136]

Alterations in CD3+ T-cells from hypoxic training appear to be fully normalized and a bit reversed with 5,000mg Reishi supplementation"

Pam

 

[Hip]

Mitochondrial complex III is essential for suppressive function of regulatory T cells

Given that evidence indicates mitochondrial functioning is generally impaired in ME/CFS (which I guess will mean all four mitochondrial complexes are working under par), perhaps this will also reduce T-reg functioning, and thus might help explain why ME/CFS patients often experience increased allergies or autoimmune diseases (POTS for example may well be autoimmune).

 

[ljimbo423]

It looks like ubiquinol, QH2, (the reduced form of coq10), is the substrate that is needed for mitochondrial complex III to work. Complex III also plays a critical role in the generation of ATP.

Complex III
In Complex III (cytochrome bc1 complex or CoQH2-cytochrome c reductase; EC 1.10.2.2), the Q-cycle contributes to the proton gradient by an asymmetric absorption/release of protons. Two electrons are removed from QH2 at the QO site and sequentially transferred to two molecules of cytochrome c, a water-soluble electron carrier located within the intermembrane space.

https://en.wikipedia.org/wiki/Electron_transport_chain#Complex_III

 

[used_to_race]

Is there any research that suggests Treg number or function is affected in ME/CFS or a subset thereof? I had my Treg count checked by a really good immunologist here in LA who is not an ME/CFS skeptic, and I appeared to be in the middle of the normal range. I'm not sure how actual Treg function is examined or if it's possible to do so in a commercial/clinical setting. Similarly, I know there are tests out there to look at mito complex function, but I don't know how reliable they are. But it's definitely something that interests me personally. It would be really nice to have a before/after dataset that encompasses my mito function before and after getting sick (given that I was competing at a high level athletically). A big step in understanding this disease will be the forthcoming findings on T cell clonal expansion, and I don't think Tregs are subject to clonal expansion. From the wikipedia on Tregs:

Another control mechanism is through the IL-2 feedback loop. Antigen-activated T cells produce IL-2 which then acts on IL-2 receptors on regulatory T cells alerting them to the fact that high T cell activity is occurring in the region, and they mount a suppressory response against them. This is a negative feedback loop to ensure that overreaction is not occurring. If an actual infection is present other inflammatory factors downregulate the suppression. Disruption of the loop leads to hyperreactivity, regulation can modify the strength of the immune response.[23] A related suggestion with regard to interleukin 2 is that activated regulatory T cells take up interleukin 2 so avidly that they deprive effector T cells of sufficient to avoid apoptosis.

I would be interested to know which "other inflammatory factors" can downregulate Treg immune suppression, and how this can be measured. Since my Treg numbers appear to be okay, induction of more Tregs would be compensatory at best. Guess I need to read this paper.