Omicron variants evolve strategies to evade T-cell immunity

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Like many other viruses that have developed strategies to evade T cell-mediated clearance by humans, the SARS-CoV-2 virus also has the ability to evade CD8 T cells. CD8 T cells play a major role in reducing viral load and eliminating infection by detecting and killing infected cells. CD8 T cells cannot protect against infection.

A study recently published in Proceedings of the National Academy of Sciences (PNAS) discovered that the SARS-CoV-2 virus encodes multiple viral factors that regulate major histocompatibility complex class I (MHC I) expression in host cells. MHC I plays an important role in alerting the immune system to virus-infected cells. MHC I molecules are expressed on the surface of all infected cells.

MHC I molecule

“When a virus infects a cell, one of the ways the immune system responds is by binding short sequences of viral proteins (antigens) to MHC I molecules, presenting the antigen outside the cell. Killer T Cells look for antigens within MHC I and if they find one that matches the specific one they were programmed to kill, they go ahead and kill it.” One of the tricks is to block MHC I expression and presentation. SARS-CoV-2 is no exception. The SARS-CoV-2 virus has evolved multiple strategies to inhibit MHC I expression, which is not seen in influenza viruses. Suppression of MHC I is specific to infected cells and varies by virus strain.

“Our data showed that MHC I suppression is mediated by a number of viral gene products and affects only infected cells. It reflects a specific survival mechanism of SARS-CoV-2,” tweeted Dr. Akiko Iwasaki, an immunologist at Yale University and corresponding author of the paper.

“What does this mean? Immune evasion from CD8 T cells allows the virus in infected cells to better survive in the host. The virus has a secure niche for long-term replication. Antiviral or antibody therapy should be employed to eliminate such persistent reservoirs,” she said in another tweet.

“excellent ability”

The ancestral strain, first discovered in Wuhan, China, and several other mutants that appeared later, already had the ability to escape T-cell-mediated immunity by reducing MHC I expression. , BA.2.12.1, XAF, and BA.4) possessed a ‘superior ability’ to suppress surface MHC I levels of virus-infected cells compared to ancestral strains and other mutants. I was. In addition to being more capable of evading neutralizing antibodies, Omicron subvariants are better able to evade recognition by killer T cells.

A team led by Dr. Iwasaki looks for the molecular mechanism of enhanced MHC I inhibition by omicron subvariants and identifies a common mutation in the E protein (T9I) that is common to all omicron subvariants used in the study. Did.

“We found that the T9I mutation within the E protein greatly enhances the degree of MHC I downregulation. , highlighting the ubiquitous ability to mediate MHC I evasion, and the superior ability of omicron subspecies in acquiring MHC I evasion,” they wrote.

Mice infected with SARS-CoV-2 (MA10) showed a complete abolition of MHC I elevation in infected lung epithelial cells, unlike influenza virus-infected lung epithelial cells. Dr. Iwasaki tweeted.

avoidance strategy

“We have demonstrated that the ability to reduce MHC I expression remains unchanged throughout the evolution of the pre-omicron concern variant. point of view,” they wrote.

First, the virus employs multiple redundant strategies to suppress MHC-I expression. Second, MHC I downregulation not only impairs the recognition of dead infected cells by cytotoxic T lymphocytes (CTL), but it can also impair T cell priming.

“Third, given that the variants of concern, with the exception of the Omicron subvariant, have not evolved further to downregulate MHC I more potently than the original strain, the SARS-CoV-2 progenitor Strains were already fully equipped to escape T-cell mediated immunization with respect to downregulation of MHC-I expression, with less evolutionary pressure to further optimize evasion strategies,” they wrote. ing.

“Our study provided evidence for inhibition of MHC I upregulation in SARS-CoV-2-infected cells in both in vitro and in vivo settings,” they said.

“The cellular mechanisms and consequences of enhanced MHC I inhibition by omicron mutants on infection and disease remain to be elucidated,” they write.