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Since SARS-CoV-2 appeared, researchers have tried to understand why the immune system sometimes does more harm than good during infection. When SARS-CoV-2 infiltrates the body, the innate immune system triggers a broad and nonspecific attack against intruders. The waves of signaling molecules that cause inflammation alert the adaptive immune system to mount a precise attack against the pathogen, which is when the viral particles are intercepted and the infected cells are eliminated.
The adaptive immune system responds to pathogens in an antigen-specific way to develop protective immunity. It consists of three main types of lymphocytes:
- B cells that produce antibodies
- CD4 + T cells (helper T cells)
- CD8 + T cells (cytotoxic T cells and killer T cells)
Evaluations of antigen-specific T cells and neutralizing antibodies are still lacking in acute COVID-19, according to researchers at the La Jolla Institute of Immunology.
To assess the three arms of the antigen-specific adaptive immune response to SARS-CoV-2 and to correlate immune responses with severity of COVID-19 disease, the researchers collected blood samples from 50 COVID-19 patients and analyzed the three branches of the adaptive immune system. . The cohort included cases in a range of severity of COVID-19 disease.
“It was particularly important for us to capture the full range of disease manifestations, from mild to severely ill, in order to identify the differentiating immunological factors,” explained co-first author and infectious disease specialist Dr. Sydney Ramirez, PhD , who spearheaded the collection of samples. .
The researchers found that broad and coordinated adaptive immune responses among the three branches of the adaptive immune system were associated with less severity of COVID-19 disease. They suggest that CD4 + and CD8 + T cells are key to the control and elimination of acute infection and can help produce high-quality neutralizing antibodies.
“When we analyzed a combination of all of our data on the 111 measured parameters, we found that, in general, people who mounted a more comprehensive and well-coordinated adaptive response tended to do better,” said co-first author and postdoctoral researcher Carolyn Moderbacher. , Doctor. “A strong SARS-CoV-2-specific T-cell response, in particular, was predictive of milder disease. Individuals whose immune responses were less coordinated tended to have worse outcomes.”
A multi-layered virus-specific immune response is important to control the virus during the acute phase of infection and reduce the severity of COVID-19 disease. Image courtesy of Crotty Lab / Cell Press.
Interestingly, the researchers found no evidence that adaptive immune cells are causally involved in the pathogenesis of COVID-19 (i.e. cytokine storm). In the cohort, hospitalized patients had CD8 + T cell response cytokine profiles similar to nonhospitalized patients, and TH2 and TH17 cytokines of CD4 + T cell responses were normal. In fact, the team observed a totally opposite effect when strong CD4 + and CD8 + T-cell responses specific to SARS-CoV-2 were associated with low disease severity.
Aging and adaptive immune responses in COVID-19
In the study, the low abundance of naive T cells was also associated with severe COVID-19 disease in the cohort. Naive T cells are inexperienced T cells that have not yet differentiated. As individuals age, the naive T cell pool decreases and, as fewer cells are available for activation, it can become increasingly difficult to respond to new pathogens.
“This could lead to a delayed adaptive immune response that cannot control a virus until it is too late to limit the severity of the disease or the magnitude of the response is insufficient,” Moderbacher explained.
“People over the age of 65 were much more likely to have a poor T-cell response and a poorly coordinated immune response, and thus have a much more severe or fatal COVID-19,” said lead author Shane Crotty, PhD, Professor at The Jolla Institute for Infectious Diseases and Vaccines Research Center. “Therefore, part of the massive susceptibility of the elderly to COVID-19 appears to be a weak adaptive immune response, which may be due to fewer naïve T cells in the elderly. With increasing age, the cell reservoir T that can be activated against a specific virus decreases and the body’s immune response becomes less coordinated, which appears to be a factor that makes older people drastically more susceptible to severe or fatal COVID-19. “
Vaccines and adaptive immune responses
Most human vaccines work on the basis of protective antibody responses, with neutralizing antibodies being the most common mechanism of action. Antibodies in the vaccine provide protective immunity when present prior to exposure to a pathogen. Once the virus appears, the vaccine-induced antibodies are ready to intercept it.
Therefore, many COVID-19 vaccines in development focus on producing strong neutralizing antibody responses. However, almost all the antibody responses and memory of affinity matured B cells are dependent on CD4 + T cells and are therefore essential for vaccines.
Separately, studies have shown that CD8 + T cells are important in developing protective immunity against viral infections. The results of the study also indicate that, while neutralizing antibodies play a role in the resolution of acute COVID-19, they appear to be less important than the CD4 + or C8 + T cells of SARS-CoV-2.
“Therefore, these findings indicate that it is plausible that T cells are more important in natural SARS-CoV-2 infection, and the most important antibodies in a COVID-19 vaccine, although it is also plausible that the responses of T cells against this virus are important in both cases, “said Crotty.
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