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Broad and strong memory CD4+ and CD8+ T cells induced by SARS-CoV-2 in UK convalescent individuals following COVID-19
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In the second study, scientists led by Tao Dong, an immunologist at the Medical Research Council (MRC), in Britain, went hunting for T-cells. These get less press than antibodies, but play an equally vital role in battling infections and securing long-term protection. (Their importance is vividly demonstrated by HIV, which targets and kills them.)
As described in Nature Immunology, the researchers compared blood samples from 28 mild and 14 severely ill covid-19 patients, as well as 16 healthy donors. The paper describes a “robust” T-cell response in infected people and, as with the Icelandic work, different responses in those who developed mild and severe cases of the illness. Specifically, mild cases were characterised by more CD8+ cells, which kill infected cells directly, rather than CD4+ ones, which regulate the immune response more generally. The MRC study found T-cells that could recognise eight separate parts of the virus, including the spike protein that allows it to penetrate human cells. That target list could offer useful hints for refining vaccines in future.
Al Edwards, an immunologist turned biochemical engineer at the University of Reading (who was not involved with either paper), is cautiously optimistic. The immune response to the disease seems to be working roughly as expected, he says. If that continues, then vaccines developed to trigger long-lasting immunity should work—at least in theory.
In practice, it is still too early to celebrate. Dr Edwards warns that immunology has never been a predictive science. There is no test that can show definitively that a vaccine will work short of actually trying it in the real world.
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Broad and strong memory CD4+ and CD8+ T cells induced by SARS-CoV-2 in UK convalescent individuals following COVID-19
Nature Immunology Sept 4 2020
The role of T cell immune responses in disease pathogenesis and longer-term protective immunity is currently poorly defined, but essential to understand in order to inform therapeutic interventions and vaccine design.
Taken together, this study has demonstrated strong and broad SARS-CoV-2-specific CD4+ and CD8+ T cell responses in the majority of humans who had recovered from COVID-19. The immunodominant epitope regions and peptides containing T cell epitopes identified in this study will provide critical tools with which to study the contribution of SARS-CoV-19-specific T cells in protection and immune pathology. The identification of non-spike dominant CD8+ T cell epitopes suggests the potential importance of including non-spike proteins such as NP, M and ORFs in future vaccine designs.
This study demonstrates the presence of robust memory T cell responses specific for SARS-CoV-2 in the blood of donors who have recovered from COVID-19. The broader and stronger SARS-CoV-2-specific T cell responses in patients who had severe disease may be the result of higher viral loads and may reflect a poorly functioning early T cell response that failed to control the virus, in addition to other factors such as direct virus-induced pathology associated with larger viral inoculums or poorer innate immunity. Alternatively, it is possible that the T cell response was itself harmful and contributes to disease severity. Consistent with recent reports from Grifoni et al.17 and Sekine et al.23, a particularly high frequency of spike protein-specific CD4+ T cell responses was observed in patients who had recovered from COVID-19. This is very similar to influenza virus infection, where viral surface hemagglutinin elicited mostly CD4+ T cell responses, whereas the majority of CD8+ T cell responses were specific to viral internal proteins24. Understanding the roles of different subsets of T cells in protection or pathogenesis is crucial for the prevention and treatment of COVID-19. The timing and strength of the first T cell responses could be critical in determining this balance at an early stage of the infection.
Evidence supporting a role for T cells in COVID-19 protection and pathogenesis is currently incomplete and sometimes conflicting3,11,12,13,14. To date, there have been few studies analyzing SARS-CoV-2-specific T cell responses and their role in disease progression15, although virus-specific T cells have been shown to be protective in human influenza infection16. In a study of CD4+ and CD8+ T cell responses to SARS-CoV-2 in non-hospitalized convalescent individuals, Grifoni et al.17 found that all recovered patients established CD4+ responses and 70% established CD8+ memory responses to SARS-CoV-2. SARS-CoV-2-specific CD4+ T cell responses were also frequently observed in unexposed participants in their study, suggesting the possibility of pre-existing cross-reactive immune memory to seasonal coronaviruses. In Singapore, Le Bert et al.18 found long-lasting T cell immunity to the original SARS coronavirus nucleoprotein (NP) in those who were infected in 2003. These T cells cross-reacted with SARS-CoV-2 NP, and T cells cross-reactive with non-structural proteins 7 and 13 of other coronaviruses were also present in those uninfected with either of the SARS coronaviruses18.
Abstract
The development of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines and therapeutics will depend on understanding viral immunity. We studied T cell memory in 42 patients following recovery from COVID-19 (28 with mild disease and 14 with severe disease) and 16 unexposed donors, using interferon-γ-based assays with peptides spanning SARS-CoV-2 except ORF1. The breadth and magnitude of T cell responses were significantly higher in severe as compared with mild cases. Total and spike-specific T cell responses correlated with spike-specific antibody responses. We identified 41 peptides containing CD4+ and/or CD8+ epitopes, including six immunodominant regions. Six optimized CD8+ epitopes were defined, with peptide–MHC pentamer-positive cells displaying the central and effector memory phenotype. In mild cases, higher proportions of SARS-CoV-2-specific CD8+ T cells were observed. The identification of T cell responses associated with milder disease will support an understanding of protective immunity and highlights the potential of including non-spike proteins within future COVID-19 vaccine design
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