Immune function remodeled by mitochondrial shape

The research, led by Erika Pearce, Ph.D., at the Bloomberg~Kimmel Institute for Cancer Immunotherapy at the Johns Hopkins Kimmel Cancer Center, suggests that learning how mitochondria impact Th17 cells is key to understanding how to control them.

The study, published Sept. 28 in the journal Nature, identifies several avenues for trying to influence the behavior of these important cells, with the goal of dampening their autoimmune activity.

When a T cell is first exposed to an enemy, it responds to signals from the enemy and the environment to become one of several types of specialized T cells, each armed with distinct functions in the immune response. While all T helper cell subtypes are crucial to the body's fight against foreigners, their imbalance can also cause disease, including type 1 diabetes, asthma, allergies and chronic inflammation.

"If we could control T cells, we could arguably control many, if not most, infections, autoimmunities and cancers," says Pearce, the study's senior author and a Johns Hopkins Bloomberg Distinguished Professor in the Department of Oncology and the Department of Biochemistry and Molecular Biology.

The study began when researchers in Pearce's laboratory, which was then at the Max Planck Institute in Freiburg, Germany, noticed a trait peculiar to Th17 cells. Among three main T effector cell types, only Th17 cells had elongated mitochondria; that is, their inner powerplants were fused together into larger structures. "That was strange because elongated mitochondria are usually seen in resting cells and not in activated cells," says first author Francesc Baixauli, Ph.D., a former postdoctoral fellow at the Max Planck Institute.

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

To confirm this result in an organism, the researchers deleted the OPA1 gene in mice and promoted a disease in these animals that models human multiple sclerosis, which is driven by their Th17 cells. With OPA1 deleted, not only did their cells stop making IL-17, but their disease symptoms abated.

Wondering how OPA1 deletion stopped the production of IL-17, the team first thought that the cells' mitochondria simply weren't producing enough energy. However, they found that OPA1 deletion did not affect energy production, and that OPA1 was crucial to the production of IL-17 regardless of whether the cells' metabolic activity was high or low. Then, they found that a central biochemical process occurring in the mitochondria had been altered, causing the buildup of a metabolite known to influence DNA and the transcriptional program of the cell. "That molecule was dampening the ability of the cell to read its DNA, and consequently IL-17 was no longer produced," says Baixauli.

To identify the connection between these responses and OPA1 deletion, the researchers compared proteins produced by normal Th17 cells and those without OPA1. In cells missing OPA1, they found a large increase in the activated form of the protein LKB1, which is a metabolic sensor that regulates cellular metabolism, cell division and mitochondrial function. When they deleted both OPA1 and LKB1 from cells, IL-17 production was restored, and the mitochondrial processes returned to normal.

"We think that LKB1 senses mitochondrial stress and alters the mitochondria's biochemical reactions appropriately, which affects the production of IL-17," says Pearce. "We now have a short list of molecules known to influence this key aspect of Th17 function, which can be the tipping point between its helpful and harmful roles. Our future research will continue to explore these relationships so that we can hopefully one day therapeutically modify them."

Other researchers were Klara Piletic, Daniel J. Puleston, Matteo Villa, Cameron S. Field, Lea J. Flachsmann, Andrea Quintana, Nisha Rana, Joy Edwards-Hicks, Mai Matsushita, Michal A. Stanczak, Katarzyna M. Grzes, Agnieszka M. Kabat, Mario Fabri, George Caputa, Beth Kelly, Mauro Corrado, Yaarub Musa, Katarzyna J. Duda, Gerhard Mittler, David O'Sullivan, Thomas Jenuwein and Joerg M. Buescher at the Max Planck Institute, and Hiromi Sesaki, Edward J. Pearce and David E. Sanin at The Johns Hopkins University.

The research was supported by the Max Planck Society, the Leibniz Prize, the National Institutes of Health (R01AI156274 and R35GM144103), The Johns Hopkins University and a Bloomberg Distinguished Professorship, a Marie Sklodowska-Curie Actions individual fellowship, a Sir Henry Wellcome fellowship and an Alexander von Humboldt postdoctoral fellowship.

Erika Pearce is a member of the ImmunoMet Therapeutics Scientific Advisory Board, and Erika Pearce and Edward Pearce are founders and scientific advisers to Rheos Medicines.