Nature reshapes mitochondria to affect the immune system

A new study of immune system Th17 cells suggests that the shape and function of their mitochondria (the dynamics of cells) are important in autoimmune and inflammatory diseases such as multiple sclerosis
.
T-Assist 17 (Th17) cells are CD4+ T immune cells that work together to help produce antibodies, activate enemy phagocytes, and recruit more soldiers to the front lines
.

The study, led by Dr.
Erika Pearce of Johns Hopkins University's Kimmel Cancer Center, shows that understanding how mitochondria affect Th17 cells is key
to understanding how to control them.
The study, published Sept.
28 in the journal Nature, identified several ways to try to influence the behavior of these important cells with the goal of suppressing their autoimmune activity
.

When a T cell is first exposed to an enemy, it responds to signals from the enemy and the environment, becoming one of several specialized T cells, each with a different function
in the immune response.
While all helper T cell subtypes are essential for the body to fight foreign cells, their imbalance can also lead to diseases including type 1 diabetes, asthma, allergies, and chronic inflammation
.

"If we can control T cells, we can say we can control a lot, if not most, of infections, autoimmunity and cancer," Pearce said
.

The study began with researchers in Pearce's lab, then at the Max Planck Institute in Freiburg, Germany, who noticed a feature
specific to Th17 cells.
Of the three main T-effector cell types, only Th17 cells have elongated mitochondria; That is, their internal power units are fused into larger structures
.
"This is strange because elongated mitochondria usually appear in stationary cells, not in activated cells," said first author Francesc Baixauli, Ph.
D.
, a former postdoc
at the Max Planck Institute.

The researchers knew that the OPA1 gene regulates mitochondrial fusion, so they deleted it in Th17 cells, finding that their mitochondria reverted to a more fragmented size and shape
.
However, these cells also stopped their primary job – producing the signaling molecule interleukin-17 (IL-17
).

To confirm this result in organisms, the researchers deleted the OPA1 gene from mice and promoted a disease in these animals that mimics human multiple sclerosis, which is driven by their Th17 cells
.
When OPA1 was removed, not only did their cells stop making IL-17, but their disease symptoms were alleviated
.

To see how the deletion of OPA1 prevented the production of IL-17, the team first thought that the mitochondria of the cells simply did not produce enough energy
.
However, they found that the absence of OPA1 does not affect energy production, and that OPA1 is critical
to the production of IL-17 regardless of whether the metabolic activity of cells is high or low.
They then found that a central biochemical process that occurs in the mitochondria is altered, leading to the accumulation
of a metabolite known to affect DNA and cell transcription programs.
"This molecule inhibits the cell's ability to read its DNA and therefore no longer produces IL-17," Baixauli said
.

To determine the link between these reactions and OPA1 deletions, the researchers compared the proteins
produced by normal Th17 cells and Th17 cells without OPA1.
In cells lacking OPA1, they found a significant increase in the activated form of the LKB1 protein, a metabolic sensor
that regulates cell metabolism, cell division, and mitochondrial function.
When they removed both OPA1 and LKB1 from the cells at the same time, IL-17 production was restored and mitochondrial processes were restored to normal
.

"We believe that LKB1 senses the pressure of mitochondria and appropriately alters the biochemical reactions of mitochondria, thereby affecting the production
of IL-17," Pearce said.
We now have a list of known molecules that can affect this key aspect of Th17's function, which could be the tipping point
between its beneficial and harmful effects.
Our future research will continue to explore these relationships, hopefully one day we can improve them
therapeutically.
”