2CoV-2CoV-1MERSKiller T cellsHKU1OC43NL63229ESARS-CoV-2 in uninfected individuals harbouring the immune factor HLA-A24-including a large proportion of Japanese.Two years into the COVID-19 pandemic, the disease has now spread to almost all corners of the globe. Its im-pact, however, has been disproportionate. Some parts of Asia, including Japan, for example, have experienced lower rates of death and serious illness compared to several Euro-pean nations and minority racial groups in the US. Under-standing the cause of this disparity could provide ways to boost the immunity of vulnerable populations.One biological factor linked to disease susceptibility is the human leukocyte antigen (HLA) subtype HLA-A24, a cell-surface protein that activates T cells with “killer” activity in the event of infection. Intriguingly, HLA-A24 is found in about 60% of Japanese compared to just 10% to 20% of Europeans and Americans.Shin-ichiro Fujii, Team Leader of the Laboratory of Im-munotherapy at IMS, surmised that studying the immune responses of HLA-A24-positive individuals may provide clues about how Asian populations like Japanese have largely avoided severe COVID-19. “Specifically, we wanted to know if pre-existing T cells in these people can cross-react with SARS-CoV-2 because this could lead to a more rapid immune response,” Fujii said.In their study published in Communications Biology, Fujii and his colleagues answered this question by first per-forming an in silico analysis to predict sequences located on the SARS-CoV-2 spike protein that can bind strongly to HLA-A24. The team identified six epitopes to put to the test.When exposed to immune cells from healthy HLA-A24-positive individuals who had never been infected with SARS-CoV-2, only one of the six epitopes, called QYI, acti-vated killer T cells. A more fine-grained comparison of the epitopes showed that QYI was also the only one to share sequence similarities with several seasonal coronaviruses.The researchers’ findings suggest that T cells may “re-member” sequences that are common between SARS-CoV-2 and its family members, even in people who have not been exposed to the new virus. In fact, the team went on to find a whole library of epitopes in the region sur-rounding QYI that both share sequences with seasonal coronaviruses and stimulate strong T cell activity.When the group performed the same tests on immune cells from HLA-A24-positive patients with haematologi-cal malignancies, who have a higher risk of COVID-19 infection and death, they found much lower levels of cross-reactivity. All hope is not lost, however, because while only 14.8% of patients showed T cell activity against QYI, more than 65% mounted a response to the library of epitopes the team identified on the spike protein.“A mixture of the immunodominant epitopes we identi-fied could be used to immunise immunocompromised pa-tients,” Fujii said, offering hope of better protecting suscep-tible populations against COVID-19. Currently, however, these findings are only applicable to individuals with HLA-A24. The next step, Fujii says, will be to look at other HLA subtypes.Figure: Killer T cells that specifically recognize a peptide on SARS-CoV-2 can cross-react with other coronavirusesA peptide on SARS-CoV-2 called QYI activates killer T cells in blood samples taken from HLA-A24-positive unexposed healthy donors. As QYI shares sequence similarities with several other coronaviruses, QYI-specific T cells can cross-react with these family members (SARS-CoV-1, MERS, HKU1, OC43, NL63, and 229E). This suggests that T cells may “remember” sequences that are common between SARS-CoV-2 and other human coronaviruses, even in people who have not been exposed to the new virus.Original paper:Shimizu K, Iyoda T, Sanpei A, Nakazato H, Okada M, Ueda S, Kato-Murayama M, Murayama K, Shirouzu M, Harada N, Hidaka M and Fujii S. Identification of TCR repertoires in functionally competent cytotoxic T cells cross-reactive to SARS-CoV-2. Commune Biol 4, 1365 (2021)Killer T cells that specifically recognize a peptide on SARS-CoV-2 can cross-react withother coronavirusA peptide on SARS-CoV-2 called QYI activateskiller T cells in blood samples taken from HLA-A24-positive unexposed healthy donors. As QYI shares sequence similarities with several other coronaviruses, QYI-specific cells can cross-react with these family members (SARS-CoV-1, MERS, HKU1, OC43, NL63, and 229E). This suggests that T cells may “remember” sequences that are common between SARS-CoV-2 and other coronaviruseven in people who have not been exposed to the new virus.Shin-ichiro FujiiA protein to help T cells rememberT cells exposed to seasonal coronaviruses can recognise
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