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Instructing cells to Stop or Go
Tregs instruct other types of immune cells on when to stop and when to go. Learning how to direct the activity of Tregs has important implications for improving cancer immunotherapy as well as developing better treatments for autoimmune diseases such as rheumatoid arthritis and type 1 diabetes.
Now, a research team from the Salk Institute has uncovered for the first time a protein that controls both the survival and function of Tregs. The discovery, published in the Proceedings of the National Academy of Sciences (PNAS) the week of November 6, 2017, suggests ways to influence Tregs to ultimately make immune-related therapies more effective.
"Tregs are at the crossroads of inflammation. A lot of Tregs in the environment weaken your immune response. But, too few and you go down the road to chronic inflammation."
"Right now there are no good targets for controlling Tregs," says Nanhai He, a research associate in Evans' laboratory and the study's first author. "This finding is very new and very important, because it shows us the role of cellular metabolism in how these immune cells function."
The protein the team studied is called Lkb1 (for liver kinase B1). Kinases are enzymes that catalyze reactions inside cells. Lkb1 was previously known to play a role in cell metabolism, but until this study, investigators didn't know that it controls the functions in the immune response of Tregs.
"When we talk about metabolism, most people think about what we eat and how much we exercise. But in this case, we're looking at the metabolism of individual cells. By compromising the ability of these cells to make energy, we see profound autoimmune disorders."
In the current study, the team used mouse models that had the Lkb1 gene knocked out in their regulatory T cells. The mice showed many symptoms of autoimmune disease and died within a few weeks of birth. Further examination revealed that the normal metabolic machinery in the Tregs was disrupted. The cells had defective mitochondria--cellular power stations--and depleted levels of ATP, which is their most important fuel source.
"Through these observations, we determined the Lkb1 pathway is responsible for supplying Tregs with energy. Without it, Tregs don't have enough fuel to function."
"It turns out that Tregs require a lot of energy to do their job, which is essentially to prevent other kinds of T cells from attacking the body," adds Michael Downes, a Salk senior scientist. "This is something that wasn't previously recognized, and it's an important discovery."
Investigators say the findings have implications for both cancer immunotherapy and therapy for autoimmune diseases. In cancer, Tregs are recruited by tumors and prevent other types of T cells, including cytotoxic T cells (also called CD8 cells) from attacking and destroying cancer cells.
"To boost cancer immunotherapy, we'd like to find ways to block the Lkb1 pathway. The outcome of this inhibition would be an increased immune response from other types of T cells, which would help them to destroy tumors."
On the other hand, boosting the ability of Tregs to suppress other types of immune cells could prevent autoimmunity, by preventing these cells from attacking organs and other tissues. Boosting the Treg population also has potential to avert immune rejection after an organ transplant.
Although Lkb1 itself is difficult to target, investigators have already identified molecules downstream in the signaling pathway that could be altered with drugs. "These drugs could either inhibit or enhance the pathway, depending on what we want them to do," Zheng explains. Further research from the team will focus on development of such drugs.
Regulatory T cells (Tregs) play a critical role in maintaining immune tolerance to self-antigens and in suppressing excessive immune responses that may cause collateral damage to the host. Unlike other CD4+ T cells, Tregs have a distinct, yet-to-be-established metabolic machinery to produce energy for survival and function. Here we show that the metabolic sensor LKB1 is critical for the survival and function of Tregs through regulation of their cellular metabolism. Interestingly, AMP-activated protein kinase, the best-studied downstream kinase of LKB1, is largely dispensable for LKB1 function in Tregs; the MAP/microtubule affinity-regulating kinases and salt-inducible kinases may mediate its functions. We highlight LKB1 as metabolic regulator that links cellular metabolism to immune cell functions.
The metabolic programs of functionally distinct T cell subsets are tailored to their immunologic activities. While quiescent T cells use oxidative phosphorylation (OXPHOS) for energy production, and effector T cells (Teffs) rely on glycolysis for proliferation, the distinct metabolic features of regulatory T cells (Tregs) are less well established. Here we show that the metabolic sensor LKB1 is critical to maintain cellular metabolism and energy homeostasis in Tregs. Treg-specific deletion of Lkb1 in mice causes loss of Treg number and function, leading to a fatal, early-onset autoimmune disorder. Tregs lacking Lkb1 have defective mitochondria, compromised OXPHOS, depleted cellular ATP, and altered cellular metabolism pathways that compromise their survival and function. Furthermore, we demonstrate that the function of LKB1 in Tregs is largely independent of the AMP-activated protein kinase, but is mediated by the MAP/microtubule affinity-regulating kinases and salt-inducible kinases. Our results define a metabolic checkpoint in Tregs that couples metabolic regulation to immune homeostasis and tolerance.
Authors: Nanhai He, Weiwei Fan, Brian Henriquez, Ruth T. Yu, Annette R. Atkins, Christopher Liddle, Ye Zheng, Michael Downesa, and Ronald M. Evans.
Other researchers involved in the study were Weiwei Fan, Brian Henriquez and Ruth Yu of Salk; and Christopher Liddle of the University of Sydney.
This work was funded by the National Institutes of Health, the National Institute of Environmental Health Sciences, the Leona M. and Harry B. Helmsley Charitable Trust, the Foundation Leducq and Ipsen/Biomeasure.
About the Salk Institute for Biological Studies
Every cure has a starting point. The Salk Institute embodies Jonas Salk's mission to dare to make dreams into reality. Its internationally renowned and award-winning scientists explore the very foundations of life, seeking new understandings in neuroscience, genetics, immunology, plant biology and more. The Institute is an independent nonprofit organization and architectural landmark: small by choice, intimate by nature and fearless in the face of any challenge. Be it cancer or Alzheimer's, aging or diabetes, Salk is where cures begin. Learn more at: salk.edu.
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Skin samples from normal mice (top) whose regulatory immune cells have the Lkb1 protein (Tregs)
as compared to the skin of mice (bottom) lacking the Lkb1 protein and under attack from other immune cells (purple dots). Image credit: Salk Institute.