Insights & Outcomes: T cells, drinking risks, and COVID-19’s road ahead

This month, Insights & Outcomes launches into spring with a penetrating look at the evolution of arm muscles, the regulation of the body’s T cell receptors, attitudes about alcoholism among problem drinkers, and the possible path forward with COVID-19.

As always, you can find more science and medicine research news on Yale News’ Science & Technology and Health & Medicine pages.

A little T cell TLC

The ability to regulate the body’s T cell immune system response has led to major advances in cancer immunotherapy. Now, Yale researchers have identified how the immune system itself regulates the strength of its T cell response against invaders such as cancer and pathogens like the COVID-19 virus.

Some cancer immunotherapies target specific receptors on T cells that act as a brake on their activity. By blocking these inhibitors, T cells can mount a more aggressive attack on cancer cells. However, the way T cell receptors as a whole are regulated has not been clear.

The Yale team found that Type 1 interferons, which are part of the body’s early warning system to detect viruses, can both activate and slow T cells’ response. Using high-temporal resolution messenger RNA screening, they also pinpointed specific combinations of gene activity on the surface of T cells that determine their function.

“For instance, we can tweak T cells’ regulatory molecules and potentially prevent T cell exhaustion driven by Type 1 interferon,” said Yale’s Tomokazu Sumida, assistant professor of neurology and corresponding author of a new study in the journal Nature Immunology.

The findings can help researchers not only fine-tune the tumor-fighting abilities of T cells but also improve immune response to viral infections such as SARS-Cov-2, the virus that causes COVID-19, and treat autoimmune diseases, Sumida said. Sumida, Shai Dulberg of Tel Aviv University, and Yale’s Jonas C. Schupp are co-lead authors of the paper. David Hafler, the William S. and Lois Stiles Edgerly Professor of Neurology and professor of Immunobiology at Yale, is senior author.

A path forward from COVID-19

After two years of living with the COVID-19 pandemic, many people want to know how and when they can safely return to their pre-pandemic lives. A new report from over 50 researchers, policy leaders, and other scholars aims to answer those questions.

Three Yale researchers contributed to the report titled “Getting to and Sustaining the Next Normal: A Roadmap for Living with COVID”: Howard Forman, professor of radiology and biomedical imaging, Akiko Iwasaki, the Sterling Professor of Immunobiology and of Molecular, Cellular, and Developmental Biology, and Harlan Krumholz, the Harold H. Hines Jr. Professor of Medicine (cardiology).

“Eliminating COVID is not a realistic goal,” say the authors. “Instead, the nation must plan to mitigate its effects, prepare for variants, and build towards a next normal.” The roadmap outlines how the United States can get past the emergency phase of the pandemic, get to the next “normal,” and reduce the risks and impacts of future pandemics so that people may once again experience “the routines and joys of everyday life.”

Muscle memories

A new, Yale-led study suggests that embryonic arm muscles can reveal a wealth of information about the evolutionary histories of all species of birds, reptiles, and mammals.

A team led by former Yale doctoral student Daniel Smith-Paredes and Bhart-Anjan S. Bhullar, an assistant professor of Earth & planetary sciences, followed the embryonic development of forelimb muscles in six major groups of amniotes — animals whose embryos are protected by a membrane and do not experience a larval stage.

Despite the seeming complexity of forelimb muscle development among amniotes, the researchers discerned a number of simple, underlying patterns. “This work basically takes the muscles of the arm in all amniotes and works out their evolutionary histories using embryology,” Bhullar said. “Previously this had been an intractable problem.”

The study, which was part of Smith-Paredes’ Yale dissertation, appears in the journal Nature Ecology & Evolution.

Co-authors of the study were Miccaella Vergara-Cereghino of Yale, Ariana Lord of Harvard, and Malcolm Moses and Richard Behringer of the University of Texas.

Downplaying the risks of drinking

When people identified as so-called “problem drinkers” learn they are not genetically predisposed to alcoholism, they are more likely to downplay the risks of alcoholism, a new Yale study shows. The study highlights that receiving negative genetic tests can ironically encourage unhealthy behaviors because people may feel more invulnerable, the authors say.

Generally, problem drinkers are defined as individuals who might be susceptible to using alcohol in a way that negatively affects their life but who aren’t dependent on alcohol.

For the study, 2,100 paid participants were asked to take an online survey about their drinking behavior, how it negatively affects their work and social relationships, and how urgently it requires treatment. Participants were then asked to take a saliva test that purportedly would reveal their genetic risk for alcohol use disorder. (Participants were informed that this was a sham test immediately after the experiment was completed). When the participants were told that they were not at genetic risk for alcoholism, they subsequently discounted the harms and severity of the behavior, and they were also less willing to moderate their drinking.

No genetic tests for alcoholism are commercially available in the U.S., but for other health conditions, such as breast cancer, genetic testing companies, such as 23andMe, attempt to prevent this false reassurance by explaining that there are other non-genetic causes that can increase risk of developing the health condition, even though individuals might test “negative.”

However, the researchers also found that these types of debriefings were not effective with problem drinkers. This may be because people mistakenly believe that genetically caused alcoholism is more severe than environmentally caused alcoholism, even when the symptoms are identical, researchers concluded.

The study by Yale’s Woo-kyoung Ahn, the John Hay Whitney Professor of Psychology, and doctoral candidate Annalise Perricone was published in the journal Scientific Reports.

Shot through the heart

SPECT (single-photon emission computed tomography) is an imaging tool that shows body functions, such as how much blood is flowing to tissues and organs. It’s often used to diagnose heart disease where it can identify heart defects with reduced blood flow. To improve accuracy, SPECT can be combined with CT (computed tomography) imaging, which reduces the likelihood of mistaking image artifacts for heart defects. But CT scanners are expensive, and most SPECT scanners aren’t paired with them. Plus, CT imaging introduces its own challenges — such as radiation exposure to patients, CT image artifacts, and more.

Deep learning techniques offer a solution. In a recent study published in the European Journal of Nuclear Medicine and Molecular Imaging, Yale researchers tested new strategies for correcting SPECT images using a neural network they developed. “Our approach showed a higher accuracy and better performance than previous approaches,” said Xiongchao Chen, a Yale biomedical engineering graduate student and lead author of the study. And this was true for both general purpose cardiac SPECT, which scans the whole body, and dedicated cardiac SPECT, which only focuses on the heart.

Using deep learning techniques in this way stands to provide the accuracy of hybrid CT-paired SPECT scanners without the added cost and radiation. “And with this,” said Chi Liu, associate professor of radiology and biomedical imaging and senior author of the study, “we can substantially reduce unnecessary invasive procedures.”

Kidney clues

Although immunotherapy has significantly increased survival rates of patients with several types of cancer, some underlying conditions such as acute kidney injury (AKI) can increase risk of death among people receiving treatment with therapies such as immune checkpoint inhibitors.

However, researchers at the Yale School of Medicine have found that in a subset of cancer patients, the AKI diagnosis may not be bad news at all, but rather an indication immunotherapy is working.

The Yale team led by Dennis Moledina, assistant professor of internal medicine (nephrology) and senior author of a new paper published in the Journal for Immunotherapy of Cancer, wanted to know if a form of AKI known as acute interstitial nephritis (AIN) — thought to be caused by immune checkpoint inhibitors — could actually be a sign of a robust T cell attack on cancer cells. “There are parallels in oncology where autoimmune skin reactions in immunotherapy patients are actually associated with positive outcomes,” Moledina said.

The researchers analyzed survival rates of 2,200 patients at Yale New Haven Hospital who received treatment with immune checkpoint inhibitors. They measured mortality rates of individuals without kidney injury and those with AKI, and specifically with AIN, diagnosed with a model developed at Yale that does not require a biopsy. They found that patients with AKI had twice the mortality rate as those without AKI. However, the researchers found no difference in mortality rates among those with AIN and those without a diagnosis of acute kidney injury. The researchers estimated that about 10% of those with AKI had developed AIN as a result of cancer immunotherapy.

Yale’s Megan Baker is lead author of the paper.

Research Redux:

Getting a grip on hand function

The oxidation of volcanoes — a magma opus

Data from space unveil a global view of animals on the move

New imaging scan reveals a culprit in cognitive decline of Alzheimer’s

Wright Lab searches for evidence of neutrinoless double beta decay