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La Jolla study suggests people with severe cases of COVID-19 may have stronger long-term immunity

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A big question on people’s minds these days: How long does immunity last following infection with SARS-CoV-2, the coronavirus that causes COVID-19?

Researchers from the La Jolla Institute for Immunology and England’s University of Liverpool and University of Southampton have uncovered a clue. Their new study suggests that people with severe COVID-19 cases may be left with more of the protective “memory” T cells needed to fight reinfection.

“The data from this study suggest people with severe COVID-19 cases may have stronger long-term immunity,” said LJI professor Pandurangan Vijayanand, the study’s co-leader.

The research, published Jan. 21 in Science Immunology, is the first to describe the T cells that fight SARS-CoV-2 in “high resolution” detail.

“This study highlights the enormous variability in how human beings react to a viral challenge,” said co-leader Christian Ottensmeier, a professor at the University of Liverpool and an adjunct professor at LJI.

A new study led by scientists at the La Jolla Institute for Immunology suggests that T cells try to fight SARS-CoV-2, the coronavirus that causes COVID-19, by targeting a broad range of sites on the virus.

Since early in the COVID-19 pandemic, scientists at LJI have investigated which antibodies and T cells are important for fighting SARS-CoV-2. As experts in genomics, Vijayanand and Ottensmeier have used sequencing tools to uncover which T cell subsets may control disease severity. In October, the team published the first detailed look at how CD4+ T cells respond to the virus.

T cells called CD8+ are responsible for destroying virus-infected host cells. “Memory” CD8+ T cells also are important for protecting the body from reinfection against many viruses.

The team studied CD8+ T cells from 39 COVID-19 patients and 10 subjects who had never been exposed to the virus (their blood samples were given before the pandemic). Of the COVID-19 patients, 17 had a milder case that did not require hospitalization, 13 had been hospitalized and nine had needed intensive care unit support.

To the researchers’ surprise, they saw weaker CD8+ T cell responses in patients with milder COVID-19 cases. The researchers saw the strongest CD8+ T cell responses in the severely ill patients who required hospitalization or ICU support.

“There is an inverse link between how poorly T cells work and how bad the infection is,” Ottensmeier said. “I think that was quite unexpected.”

One could expect to see a stronger CD8+ T cell response in the mild cases, since these are where the immune system was equipped to fight off severe infection — but the study showed the opposite. In fact, CD8+ T cells in the milder cases showed the molecular signs of a phenomenon called T cell “exhaustion,” when cells receive so much immune system stimulation during a viral attack that they are less effective in doing their jobs.

Vijayanand and Ottensmeier think it is worth studying whether T cell exhaustion in the mild COVID-19 cases may hinder a person’s ability to build long-term immunity.

“People who have severe disease are likely to end up with a good number of memory cells,” Vijayanand said. “People with milder disease have memory cells, but they seem exhausted and dysfunctional, so they might not be effective for long enough.”

The new study provides a window into CD8+ T cell responses, but it is limited because it relies on the CD8+ T cells found in blood samples. As a next step, the researchers hope to shed light on how T cells in tissues hit hardest by SARS-CoV-2, such as the lungs, react to the virus. That will be important because the memory T cells that provide long-term immunity need to live in the tissues.

“This study is very much a first step in understanding the spectrum of immune responses against infectious agents,” Ottensmeier said. ◆