There have been many studies investigating the role of SARS-CoV-2 specific CD8+ T cells activated through classical MHC Class I molecules. However, there are also many studies showing that, classical MHC Class I molecules can be downregulated during infection which could limit these responses, particularly in the later stages of an infection. In a new study led by Sir Professor Andrew McMichael, Professor Jane McKeating & Associate Professor Geraldine Gillespie, researchers looked into whether CD8+ T cell responses against SARS-CoV-2 could be elicited by the non-classical MHC class I molecule, human leukocyte antigen E (HLA-E).
MHC molecules (known as HLA in humans) are expressed on most nucleated cell types in the body and are responsible for presenting antigens, or tiny fragments of proteins, to cells of the immune system. The classical MHC Class I molecules, HLA-A, HLA-B & HLA-C, present mainly antigens derived from intracellular proteins to CD8+ T Cells for activation. The non-classical MHC I molecules, such as HLA-E, mediate inhibitory or activating stimuli in natural killer (NK) cells. HLA-E primarily presents the signal sequence of classical MHC class I molecules to NK cells in inhibit their function.
In SARS-CoV-2 infection, it has been demonstrated that classical MHC class I expression is downregulated in SARS-CoV-2+ cells. This reduction in surface expression also leads to a reduction in the signal sequence presented by HLA-E, opening the possibility for HLA-E molecules to present alternative antigens. Researchers show here that HLA-E is not down-regulated by SARS-CoV-2 infection; in fact, showing some evidence that HLA-E expression may be increased in infected cells.
Looking at CD8+ T cells from patients recovered from SARS-CoV-2 infection, the researchers identified several CD8+ T cell responses that recognised HLA-E-presented antigens and were able to restrict replication of the virus. The relative protective activities of HLA-E-restricted T cells compared with the classically restricted T cells will need to be determined in the future. But this work opens new avenues for enquiry, suggesting that HLA-E restricted T cells may be able to contribute to control of virus infection, particularly in cases where the virus has adapted ways of down-regulating HLA expression.
Professor McMichael said: "HLA-E normally plays a minor role in presenting peptides to T cells in infections such as with SARS-CoV-2, but when present they can contribute to protection. Because HLA-E is the same in everyone this opens possibilities for immunotherapy which are being explored."
In the future, induction of HLA-E-restricted T cell responses by vaccines focused on the universally presented antigens could be an attractive possibility.
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