Study highlights possible Achilles' heel in key immune memory cells

March 9, 2017, Brigham and Women's Hospital
T cell
Scanning electron micrograph of human T lymphocyte or T cell. Credit: NIAID/NIH

The capacity for memory isn't exclusive to the brain. The immune system, with its sprawling network of diverse cell types, can recall the pathogens it meets, helping it to swiftly neutralize those intruders upon future encounters.

For the last several years, BWH's Thomas Kupper, MD, Chair of the Department of Dermatology, and his colleagues have been studying a unique kind of immune memory cell, known as a tissue-resident memory T (TRM) cell. Discovered more than 10 years ago by Rachael Clark, MD, PhD (also in BWH Dermatology), these cells live in , like the skin, gut and joints, and are thought to be a key source of the immune system's protective memory. Although much remains to be learned about the biology of these specialized memory T-cells, dysfunctional TRM cells are strongly implicated in , such as psoriasis, rheumatoid arthritis, and other conditions.

To uncover the key genetic signals that guide the development of TRM cells, Kupper and his colleagues, led by postdoctoral fellow Youdong Pan, PhD, took an unbiased approach. They measured the level of gene activity for every gene in the genome as the cells developed in mice. That led the team to a remarkable finding, reported in a recent issue of the journal Nature: genes involved in lipid metabolism are highly active in TRM cells, roughly 20- to 30-fold more active than in other types of T-cells. Among these genes are two key mediators of lipid uptake, fatty-acid-binding proteins 4 and 5 (Fabp4 and Fabp5).

Kupper and his colleagues teamed up with Gökhan Hotamisligil, PhD, an expert in lipid biology and metabolism at the Harvard T. H. Chan School of Public Health, to further dissect the roles of Fabp4 and Fabp5 in TRM cells. They found that TRM cells that lack both genes show a striking defect in their ability to import lipids. (Cells lacking just one of the genes are unaffected, likely because the two genes are highly related and perform overlapping functions.) Moreover, these Fabp4- and Fabp5-deficient TRM cells are significantly compromised both in their ability to protect against infection and their long-term survival in peripheral tissues.

Based on his team's recent work, Kupper says the picture that is emerging of TRM cells highlights a unique dependence on fatty acids and other lipids as an energy source. Other types of T-cells can also metabolize lipids, but they cannot take them up from the environment, as TRM cells can. This could become an important Achilles' heel for investigators to target in the future.

Drugs aimed at inhibiting lipid uptake could enable the selective removal of TRM cells from tissues, while leaving other types of T-cells intact. Current therapies for autoimmune disease are fairly broad in their activity—quieting down many types of , including TRM cells. But they work transiently, likely because TRM cells remain in place.

"I think the real potential pay off of this story is to try and use this new information therapeutically," said Kupper. "While there are treatments for autoimmune diseases that impact pathogenic tissue-resident memory T-cells, none are able to effectively remove the from tissues. We've identified the first plausible mechanism for doing just that."

Explore further: Virus infection sheds light on memory T cells living in our skin

More information: Youdong Pan et al, Survival of tissue-resident memory T cells requires exogenous lipid uptake and metabolism, Nature (2017). DOI: 10.1038/nature21379

Related Stories

Virus infection sheds light on memory T cells living in our skin

February 29, 2012
Very recently, researchers discovered an important population of immune cells called memory T cells living in parts of the body that are in contact with the environment (e.g., skin, lung, GI tract). How these "resident" memory ...

Discovery of new T-cell subtype opens window on rheumatoid arthritis

February 1, 2017
A research team led by scientists from Brigham and Women's Hospital (BWH) has carefully scrutinized the immune cells from patients with rheumatoid arthritis, revealing a striking new subset of T-cells that collaborate with ...

A leukemia drug kills cancerous T-cells while sparing normal immunity

January 25, 2012
Leukemic cutaneous T-cell lymphoma (L-CTCL) is a leukemia arising from T-cells, a type of white blood cell. This cancer can involve the skin and other organs, and patients often die within three years.

Researchers identify factors responsible for chronic nature of autoimmune disease

January 4, 2017
Researchers from Schepens Eye Research Institute of Massachusetts Eye and Ear have uncovered two factors responsible for the chronic, lifelong nature of autoimmune disorders, which tend to "flare up" intermittently in affected ...

Preventing too much immunity

December 27, 2016
Scientists at the Immunology Frontier Research Center (IFReC), Osaka University, Japan, report a new molecular mechanism that could explain the cause of some autoimmune diseases.

Autoimmunity and infections—when the body fights itself

January 6, 2017
Basel-based doctors are on the trail of a possible connection between autoimmune diseases and infections: errors can occur when immune cells absorb certain proteins from pathogen cells. These findings were reported in the ...

Recommended for you

New genetic study could lead to better treatment of severe asthma

December 12, 2018
The largest-ever genetic study of people with moderate-to-severe asthma has revealed new insights into the underlying causes of the disease which could help improve its diagnosis and treatment.

Researchers discover unique immune cell likely drives chronic inflammation

December 11, 2018
For the first time, researchers have identified that an immune cell subset called gamma delta T cells that may be causing and/or perpetuating the systemic inflammation found in normal aging in the general geriatric population ...

Macrophage cells key to helping heart repair—and potentially regenerate, new study finds

December 11, 2018
Scientists at the Peter Munk Cardiac Centre have identified the type of cell key to helping the heart repair and potentially regenerate following a heart attack.

Study identifies a key cellular mechanism that triggers pneumonia in humans

December 11, 2018
The relationship between influenza and pneumonia has long been observed by health workers. Its genetic and cellular mechanisms have now been investigated in depth by scientists in a study involving volunteers and conducted ...

New light-based technology reveals how cells communicate in human disease

December 11, 2018
Scientists at the University of York have developed a new technique that uses light to understand how cells communicate in human disease.

Immune cells sacrifice themselves to protect us from invading bacteria

December 11, 2018
Immune systems are working overtime as winter approaches. Stomach flu can turn the strongest individual into a bedridden convalescent. Viruses are spreading in kindergartens. This year's flu is approaching in full swing. ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.