Sugar and fat activate unique immune cells against viruses and bacteria

Resume: Researchers discovered two subtypes of mucosal-associated invariant T cells (MAIT) in mouse lungs. Each subtype has a distinct role: MAIT1 cells fight viruses with sugar as fuel, while MAIT17 cells fight bacteria with fat.

These findings reveal new mechanisms of immune protection and suggest that altering the balance between these two cell groups could pave the way for innovative vaccines and therapies to combat various pathogens.

Key Facts:

  1. Two different MAIT cell subtypes have been identified: MAIT1 and MAIT17, which fight viruses and bacteria, respectively.
  2. MAIT1 cells use sugar (glycolysis) as fuel when activated, while MAIT17 cells require a steady intake of fatty acids.
  3. Metabolic manipulation confirmed that changing fuel sources affected MAIT cell response, suggesting potential for future clinical application.

Source: La Jolla Institute

A population of unconventional white blood cells has recently caught the attention of immunologists and clinicians alike. Unlike conventional T cells, which circulate in our blood throughout the body, mucosal-associated invariant T cells (MAIT) are largely found in tissues where they provide immune protection against a wide variety of diseases.

MAIT cells are very common in humans. Although they make up only 2 percent of lymphocytes in the blood, MAIT cells account for 10 to 40 percent of lymphocytes in the liver and are common in tissues such as lungs. Yet much about MAIT cell biology and clinical function remains unknown.

In a new study, published in Nature cell biologyscientists at the La Jolla Institute for Immunology (LJI) examined the location, function, gene expression and metabolism of MAIT cells in the mouse lung.

“Metabolism is how your cells use fuel molecules to do their job,” says LJI instructor Thomas Riffelmacher, Ph.D., first author of the study.

“There has been a recent revolution in the field in which studies are beginning to link the function of T cells to their metabolic programming, but this had not yet been explored in MAIT cells.”

To pioneer this line of research, Riffelmacher teamed up with LJI Professor and Chief Scientific Officer Mitchell Kronenberg, Ph.D., an expert on faster-response innate T cells. Their latest work characterizes these properties in MAIT cells and how they contribute to the population’s ability to fight pathogens.

The efforts revealed two distinct “flavors” of MAIT cells: an antiviral subtype fueled by sugar and an antibacterial subtype fueled by fat. The findings may now inspire new vaccines and cell therapies that shift the balance between these two cell groups to help individuals fight specific pathogens.

A story about two cell types

MAIT cells show enhanced memory-like responses after some infections, with higher cell numbers and stronger protective responses boosting host defenses long after the pathogen has left the body. Riffelmacher initially wanted to investigate which molecular changes drove this important memory function in MAIT cells.

To do this, he delivered a live bacterial vaccine strain to a mouse model, and within days MAIT cells had grown 100 times in size in the animals’ lungs. What Riffelmacher did not expect was the emergence of two different groups of cells within this vast population.

Through an extensive series of experiments to characterize these two cell lines, several distinct properties became apparent.

One subtype of MAIT cells, located primarily along blood vessels in the lungs, elicited a type 1 immune response defined by the secretion of a cytokine called interferon-gamma (IFN-ɣ). These lymphocytes, called MAIT1 cells, specialized in fighting intracellular microbes, namely viruses such as the flu.

The other subtype of MAIT cells, found primarily in lung tissue, produced a type 17 immune response defined by the secretion of another cytokine, interleukin-17 (IL-17). MAIT17s were specialized to fight extracellular microbes, namely bacteria such as those that lead to pneumonia.

To further demonstrate their distinctive protective properties, the researchers purified MAIT1 and MAIT17 cells and transferred them into new mice. Both populations improved the animals’ immunity compared to untreated mice.

However, MAIT1s provided better protection against the flu virus, while MAIT17s provided protection against the bacteria Streptococcus pneumoniae, the most common cause of pneumonia.

Even more striking than their functional differences were their widely differing metabolic programs. Each cell type seemed to get its energy from a different source.

“I remember seeing this first set of data and thinking, ‘Wow, this is a huge difference — we need to investigate this,'” says Riffelmacher, who also serves as LJI Immunometabolism Core Director.

MAIT1s remained in a very low-energy, dormant state until activated, at which point they depended on sugar (glycolysis) to get their fuel. In contrast, MAIT17s were highly active and required constant consumption of fatty acids to generate sufficient energy through their mitochondria.

When the researchers genetically engineered white blood cell metabolism to promote glycolysis, MAIT1 cell numbers were increased, confirming that metabolism affected MAIT cell response.

What is the (clinical) benefit?

Does this mean that eating fatty foods can protect you from pneumonia? Kronenberg says diet may have some influence on the distribution of metabolites in the body, but metabolism functions differently at the cellular and organism level, so there’s no evidence that changing one’s diet would affect MAIT cell function.

But by pharmacologically adjusting the levels of these metabolites, the researchers were able to alter the animals’ MAIT cell response, which is likely better at fighting off a viral infection or bacteria.

To do this clinically in humans, the researchers propose developing vaccines to activate either MAIT1 or MAIT17 cells, or even transplanting one cell subtype into patients to boost a particular immune response.

Because MAIT cells and the main signaling protein they interact with are so highly conserved across individuals and species, they are also much less likely to elicit a graft versus host response than other types of white blood cells.

“Our hope is that in the future we will have tools to selectively enhance MAIT1s or MAIT17s so that patients can tailor their immune system to different pathogens as needed,” says Kronenberg.

Additional authors of the study, “Divergent metabolic programs control two populations of MAIT cells that protect the lung,” include Mallory Paynich Murray, Chantal Wientjens, Shilpi Chandra, Viankail C. Castelan, Ting-Fang Chou, Sara McArdle, Christopher Dillingham, Jordan Devereaux, Aaron Nilsen, Simon Brunel, David Lewinsohn, Jeff Hasty, Gregory Seumois, Christopher Benedict, and Pandurangan Vijayanand.

financing: This research was supported by the National Institutes of Health (NIH; grants AI71922, AI137230) and the Wellcome Trust (grant 210842_Z_18_Z).

About this neuroscience research news

Author: Gina Kirchweger
Source: La Jolla Institute
Contact: Gina Kirchweger – La Jolla Institute
Image: The image is credited to Neuroscience News

Original research: Open access.
“Divergent metabolic programs control two populations of MAIT cells that protect the lung” by Thomas Riffelmacher et al. Nature cell biology


Differing metabolic programs control two populations of MAIT cells that protect the lungs

Although mucosal-associated invariant T cells (MAIT) give rapid, innate-like responses, they are not preset and memory-like responses have been described for MAIT cells after infections.

However, the importance of metabolism in controlling these reactions is unknown.

Here, after lung immunization with a Salmonella vaccine strain, mouse MAIT cells expanded as single CD127Clrg1+ and CD127+Clrg1 antigen-adapted populations that differed in terms of their transcriptome, function and localization in lung tissue.

These populations remained altered from steady state for months as stable, single MAIT cell lines with enhanced effector programs and divergent metabolism. CD127+ MAIT cells engaged in an energetic, mitochondrial metabolic program, which was critical to their maintenance and IL-17A synthesis.

This program was supported by high fatty acid uptake and mitochondrial oxidation and was based on highly polarized mitochondria and autophagy.

After vaccination, CD127+ MAIT cells protected mice against Streptococcal pneumoniae infection. Klrg1+ MAIT cells had dormant but ready-to-respond mitochondria and instead depended on Hif1a-driven glycolysis to survive and produce IFN-γ. They responded independently to antigen and participated in the protection against the flu virus.

These metabolic dependencies may allow tuning of memory-like MAIT cell responses for vaccination and immunotherapy.

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