T helper 17 cells (Th17) in the immune system are a type of CD4+ T cells that together help make antibodies, activate cells that engulf enemies, and recruit more soldiers to the battlefield. A new study focusing on Th17 cells shows that the shape and function of their mitochondria play an important role in autoimmune and inflammatory diseases such as multiple sclerosis. Understanding how mitochondria affect Th17 cells is important to understanding how to control their key. They identified several pathways that sought to influence the behavior of these cells, with the aim of suppressing their autoimmune activity.
When a T cell first encounters an enemy, it responds to signals from the enemy and the environment, becoming one of several types of specialized T cells, each with unique functions in the immune response. While all helper T cell subtypes are essential for the body to fight foreign invaders, their imbalance can also contribute to disease, including type 1 diabetes, asthma, allergies and chronic inflammation.
The new study began when researchers in Pearce's lab noticed a characteristic feature of Th17 cells. Of the three main effector T cell types (Th1, Th2 and Th17), only Th17 cells have elongated mitochondria; that is, their internal energy factories are fused together to form larger structures.
The researchers knew that the OPA1 gene regulates mitochondrial fusion, so they knocked out the OPA1 gene in Th17 cells and found that their mitochondria returned to their fragmented size and shape. However, these cells also stopped their main job of producing the signaling molecule interleukin-17 (IL-17).
To confirm this result in vivo, they knocked out the OPA1 gene in mice and triggered a disease in these animals that mimics human multiple sclerosis, which is driven by their Th17 cells. After knocking out OPA1, not only did their cells stop making IL-17, but their disease symptoms also decreased.
To understand how knockout of OPA1 prevented IL-17 production, the authors first thought that the mitochondria of Th17 cells were simply not producing enough energy. However, they found that the absence of OPA1 did not affect energy production, and that OPA1 was critical for IL-17 production regardless of whether the metabolic activity of these cells was high or low. They then found that a core biochemical process that occurs in mitochondria was altered, leading to the accumulation of a metabolite known to affect DNA and the cell's transcriptional program.
To determine the link between these responses and OPA1 loss, the authors compared the protein produced by normal Th17 cells and Th17 cells without OPA1. In Th17 cells lacking OPA1, they found a massive increase in the activated form of the protein LKB1, a metabolic sensor protein that regulates cell metabolism, cell division and mitochondrial function. When they knocked out both OPA1 and LKB1 from Th17 cells, IL-17 production was restored and mitochondrial processes returned to normal.
The researchers concluded that LKB1 senses mitochondrial stress and appropriately alters mitochondrial biochemical responses, which affect IL-17 production. There is now a brief list of molecules known to affect this key aspect of Th17 cell function, which may be the tipping point between its beneficial and detrimental effects. Future research will continue to explore these relationships so that they can one day be therapeutically modified.