Immune-killing cells switch found


Scientists have uncovered the mechanism that controls whether cells that are able to suppress immune responses live or die.

The discovery of the cell death processes that determine the number of ‘regulatory T cells’ an individual has could one day lead to better treatments for immune disorders.

Regulatory T cells are members of a group of immune cells called T cells. Most T cells actively respond to clear the body of infections. By contrast, regulatory T cells are considered to be immune suppressing cells because they can ‘switch off’ an immune response to a particular molecule. This immune suppression is important for preventing inappropriate immune attack of the body’s own tissues, which is the underlying cause of autoimmune diseases such as lupus and type 1 diabetes.

A shortage of regulatory T cells is linked with the development of autoimmune and inflammatory conditions, while some people with higher than normal numbers of regulatory T cells cannot fight infections properly.

Dr Daniel Gray and Ms Antonia Policheni from the Walter and Eliza Hall Institute’s Molecular Genetics of Cancer and Immunology divisions made the discovery about how regulatory T cell numbers are controlled as part of an international team of researchers jointly led by Dr Gray and Dr Adrian Liston who is head of the Flanders Institute for Biotechnology (VIB) Laboratory for Autoimmune Genetics at the University of Leuven, Belgium. They found that regulatory T cells are constantly being produced in the body, but their numbers are held steady by a process of cell death. The findings are published in the journal Nature Immunology.

Cell death, or apoptosis, is important in many immune cell types for the removal of excess, defective or damaged cells. The decision of these cells on whether to live or die is controlled by a family of proteins called the ‘Bcl-2 protein family’. This includes proteins that can either promote cell survival or trigger cell death, in response to many different stimuli.

Dr Gray said the team had discovered that Bcl-2 family proteins were important determinants of regulatory T cell numbers. “Regulatory T cell death is highly dependent on the activity of two opposing Bcl-2 family proteins, called Mcl-1 and Bim,” he said. “Mcl-1 is required for regulatory T cell survival, allowing them to suppress unhealthy immune responses, while Bim triggers the death of regulatory T cells. Without Mcl-1 activity, regulatory T cell numbers fall, provoking lethal autoimmune disease. Conversely, if Bim activity is lost, regulatory T cells accumulate in abnormally high numbers.”

Dr Liston said the finding was exciting, because it opened up new ways to control regulatory T cell numbers in disease. “Already, there is considerable interest in a new class of agents, called ‘BH-3 mimetics’ that target Bcl-2-like molecules including Mcl-1,” he said. “If agents that can influence regulatory T cell survival can be developed, we could see new ways to suppress autoimmune disease, by boosting regulatory T cell numbers, or to enhance beneficial immune responses, by silencing regulatory T cells.”

The research was funded by the Australian National Health and Medical Research Council, the Victorian government, the European Union, the Belgian Government, and the VIB.

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  1. This is really interesting.

    It could open up new ways to measure the influences driving the availability of regulatory T-cells as a proxy for measuring the status of elements of the overall immune system. It seems like it could be very useful for clinicians to know this. Maybe as quick diagnostic spot check similar to other blood tests.

    This work also fits in with a growing awareness that populations consuming large amounts of grain-based foods may be an underlying cause of the increasingly prevalent diseases associated with autoimmunity. Theory being that grain-based foods have evolved a great variety of defensive proteins, capable of disrupting and penetrating the gut walls of mammalian browsing predators, which then internally disrupt various signalling mechanisms that affect immunity. Something of great relevant for GMO research in agriculture.

  2. The importance of this is the knowledge may eventually be applied to thousands of diseases.

    It is interesting to note that governments funded the research.

  3. Pete H, do you have any references for the ‘grain based foods, defensive proteins’ theory? It sounds intriguing.

  4. Some other references:

    Most of the work in this area is epidemiology. i.e. Inferences based on marginally significant statistical relationships.
    Which is why this particular item is so interesting. Comes from a different direction and indicates actual mechanisms rather than effects estimated only from correlations.

    One you’re aware of these kinds of potential mechanisms then you can make reasonable assumptions that evolutionary processes could enable these mechanisms to be exploited (and subsequently out manoeuvred by compensating evolutionary processes). This is an area where the complexity of molecular processes in cells would exceed most readily feasible methods of current research. So it’s possible that mere informed speculation can be at least as likely to be true as ‘real’ science.

    There was some publicity very recently about the poor quality of this kind of research being performed in China, where some rice proteins were claimed to have been detected in the blood immediately following a rice meal, and potentially interfering with allergy responses. But the research has been unable to be successfully repeated. (There was some discussion on this blog within the last couple of months – so there might be a reference linked from the original item.)

    On the other hand there’s other research that indicates that pretty much most statistically based research is dodgy:
    Why Most Published Research Findings Are False

    I think that what’s really going on with some autoimmune diseases is the kind of thing that would be very difficult to track down. If only because the kinds of feedback and control pathways discussed in this press release are so incredibly intricate and subtle. Plus the necessary degree of gut permeability to intact foreign protein from food might be very abnormal, resulting from disease or injury, and the protein molecules need be so incredibly few and effectively undetectable. Maybe the work needs to be repeated with people suffering from autoimmune diseases rather than a tiny subset from random members of the healthy population.

    There’s some interesting discussion from the ‘This Evolutionary View of Life’ website:

    The Science Behind the Paleolithic Diet

    Robb Wolf talks about how evolutionary science saved his life

    The guy in the second YouTube interview mentions an example of a potential autoimmune disease dietary association with Lupus, MS, arthritis, Huntington’s , Parkinsons, & Alzheimers. There’s a possibility that many of the effects of these genetic diseases might be eliminated (via bland food diet), many years before anyone gets near understanding what’s really going on.

    It seems plausible that plants would have evolved mechanisms to disturb gut permeability to inject hormonal toxins that effectively turn a predator against itself. A form of biological warfare. It’s a classic military defence strategy to get ones opponents squabbling amongst themselves. Might be some kind of evolutionary analog. Interesting that humans have evolved to savour the bitter tastes associated with toxic plant food. (Possible evidence that our ancestors got most of their nutrients from animal rather than plant sources.) But presumably similar tolerances would develop in other herbivorous browsing animals. So the relatively rapidly growing and reproducing grass type plants face unusual selection pressure to increase the sophistication of their deterrents. (Hence the risky implications for GMO grain-based agriculture.)

    On the other hand it might just be a coincidence. i.e. Disruptive plant proteins being a random effect. Autoimmune responses being just a consequence for the unfortunate few among the enormously large populations consuming massive amounts of various grain products.
    It might be difficult to track down recent research owing to the technical jargon. There’s a recent pop science book oriented around this subject: Wheat Belly – William Davis. With copious reference notes.

  5. Thanks Pete H. I wonder if any studies have been done comparing groups eating high volumes of cereal to such groups as the Masai who I understand have a diet high in blood and milk? Also the gauchos of Argentina are (were?) pretty much ‘beefeaters’, as I believe many in that area still are. The hunter-gatherer diet would also be low in cereals, though a current study is not so easy. I do wonder, what with the defences that plants have evolved what the safest diet is for us. Carnivore or Vegan? Lion or Lamb?

  6. Cell death, or apoptosis

    I thought that apoptosis is only one type of cell death, i.e. an actively triggered one, another (the other?) being necrosis.

  7. Quite right.

    The Paleo Diet is proving incredibly popular and effective for many people. Including generating lucrative book sales. As anyone who diets knows, you need to continually move on to the next fad very quickly or they don’t work. So there’s all kinds of fantastic stuff around in explanation. But it probably isn’t effective as a consequence of the theory that humans aren’t adapted to Neolithic agricultural practises.

    From what I understand the obvious benefits of paleo diet are an inevitable consequence of increasing dietary fat, reducing chronic over-exposure to the glycation impact of glucose and fructose, and minimising exposure to problematic proteins (most likely to be found in grass seeds). As the SciAm article says, most of it is common sense. i.e. eat your meat and veges and keep treats for special occasions instead of hourly hits. It might be better rebranded as the AD 1920’s or 1950’s diet, or the pre-television network diet. An era slightly more recent than BCE 10,000.

    The reason people ‘normally’ eat otherwise is either a consequence of poverty, or of marketing some of the world’s most highly addictive substances (convenience foods made of sugars, fats, and salt) and the politics and lobbying associated with the processed foods industry – mostly owned by tobacco companies I’ve heard. It might have been better for everyone to have let them keep the tobacco market. That way they wouldn’t have needed to inflict processed food on the rest of us.

    Most paleo fanatics are also into very competitive exercise. There’s more to the paleo fad than the food aspects.

    In reply to #7 by PERSON:

    In reply to #4 by Pete H:

    How to Really Eat Like a Hunter-Gatherer: Why the Paleo Diet Is Half-Baked

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