Omicron variants evolve strategies to evade T cell immunity

Much like many other viruses that have developed strategies to evade T cell-mediated clearance by humans, SARS-CoV-2 virus too has the ability to evade the CD8 T cells. While neutralising antibodies are responsible for preventing infection, CD8 T cells play a huge role in reducing the viral load and clearing the infection by detecting and killing infected cells. The CD8 T cells cannot prevent infection. 

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

MHC I molecules

“When a virus infects a cell, one of the ways in which the immune system responds is by attaching short sequences of proteins from the virus (antigen) to MHC I molecules, thus presenting the antigen on the outside of the cell. Killer T-cells look for antigens inside MHC I and if they find any that match the specific thing they are programmed to kill, they go ahead and kill it.” One of the common tricks that viruses use to avoid killing is to inhibit 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 the case of the influenza virus. The suppression of MHC I is specifically seen in the infected cells and varies between different viral strains.

“Our data showed that MHC I suppression is mediated by a number of viral gene products and affects only the infected cells. Such a mechanism will not lead to generalised immunodeficiency but reflects a specific survival mechanism for SARS-CoV-2,” Dr. Akiko Iwasaki, Yale University immunologist and the corresponding author of the paper, tweeted.

“What does this mean? Immune evasion from CD8 T cells could allow the virus in infected cells to survive better in the host. The virus could establish a safe niche for prolonged replication. To eliminate such persistent reservoirs, we need to employ antivirals or antibody therapy,” she said in another tweet.

‘Superior capacity’

The ancestral strain first found in Wuhan, China and a few other variants that came up later already had the ability to escape from T cell-mediated immunity by reducing the expression of MHC I. But the authors found that the Omicron subvariants (BA.1, BA.2.12.1, XAF, and BA.4) had a “superior capacity” to suppress MHC I levels on the surface of the cells infected by the virus compared with the ancestral strain and other variants. Besides being endowed with greater ability to evade neutralising antibodies, the Omicron subvariants are better at evading recognition by the killer T cells. 

Looking for the molecular mechanism of the enhanced MHC I inhibition by Omicron subvariants, the team, led by Dr. Iwasaki, identified common mutations in the E protein (T9I) which are shared among all Omicron subvariants used in the study.

“We found that T9I mutation within the E protein significantly enhanced the degree of MHC I downregulation. The results underscore the universal capacity of all SARS-CoV-2 strains to mediate the cell-intrinsic reduction of MHC I expression within the infected cells, and highlight the superior ability of the Omicron subvariants in acquiring MHC I evasion capacity,” they write. 

Mice infected with SARS-CoV-2 (MA10) showed that MHC I elevation was completely shut down in the infected lung epithelial cells unlike the lung epithelial cells infected with influenza virus. “So, here we found an intrinsically potent ability of SARS-CoV-2 to shut down the host MHC-I system,” Dr. Iwasaki tweeted. 

Evasion strategy

“We demonstrated that the ability to reduce MHC I expression remained unchanged throughout the pre-Omicron variant-of-concern evolution. These findings suggested three important perspectives on the MHC I evasion strategy of SARS-CoV-2,” they write.

First, the virus utilises multiple redundant strategies to suppress MHC-I expression. Second, MHC I downregulation may not only impair cytotoxic T lymphocytes (CTL) recognition of infected cells for killing but may also impair priming of T cells. 

“Third, given that the variant of concern had not further evolved to down-regulate MHC I more strongly than the original strain except for the Omicron subvariants, the SARS-CoV-2 ancestral strain was already fully equipped to escape from T cell-mediated immunity with respect to downregulation of MHC-I expression and is under less evolutionary pressure to further optimize the evasion strategy,” they write. 

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

“The cellular mechanisms and consequences of enhanced MHC I inhibition by Omicron variants on infection and disease remain to be determined,” they write.