Non-severe SARS-CoV-2 infection is characterised by very early T cell proliferation independent of type 1 interferon responses and distinct from other acute respiratory viruses

Abstract

The correlates of natural protective immunity to SARS-CoV-2 in the majority who experience asymptomatic infection or non-severe disease are not fully characterised, and remain important as new variants emerge. We addressed this question using blood transcriptomics, multiparameter flow cytometry and T cell receptor (TCR) sequencing spanning the time of incident infection. We identified a type 1 interferon (IFN) response common to other acute respiratory viruses, and a cell proliferation response that discriminated SARS-CoV-2 from other viruses. These responses peaked by the time the virus was first detected, and in some preceded virus detection. Cell proliferation was most evident in CD8 T cells and associated with rapid expansion of SARS-CoV-2 reactive TCRs. We found an equally rapid increase in immunoglobulin transcripts, but circulating virus-specific antibodies lagged by 1-2 weeks. Our data support a protective role for rapid induction of type 1 IFN and CD8 T cell responses to SARS-CoV-2.

T cell immunity to SARS-CoV-2

“…Likewise, early induction of a functional (IFN-γ-producing) CD4 + T cell response are found much earlier in patients with mild disease and correlates with viral clearance [ 20 ]. These data go in line with recent preliminary data suggesting that very rapid induction of CD8 + T cells could be a cause of asymptomatic disease [ 30 ]. A new study found that severe COVID-19 is not preferentially associated with the quantity of the CD4 + T cell response, but rather poor polyfunctionality and proliferative capacity, as well as enhanced immune activation [ 31 ].…”

“…Furthermore, sampling of peripheral blood from individuals prior to and after SARS-CoV-2 infection demonstrate that pre-existing CD4 + and CD8 + T cells can be recalled and expanded after infection [ 66 , 68 ], but do not seem to preclude the generation of a highly polyclonal primary T cell response after infection [ 66 ]. An early activation of SARS-CoV-2-specific CD4 + and CD8 + T cells has been associated with fast viral clearance and a milder clinical disease outcome [ 20 , 30 ], but whether an early T cell response stems from the activation of pre-existing T cell responses or rapid priming of naïve responses has remained unclear. A new study suggest, however, that persons with cross-reactive CD4 + T cell responses demonstrate a higher frequency of SARS-CoV-2-spike-specific CD4 + T cells and neutralizing antibody responses post infection [ 67 ].…”

Pre-existing polymerase-specific T cells expand in abortive seronegative SARS-CoV-2 infection

“…Recent HCoV infection is associated with reduced risk of severe COVID-19 infection 49 , likely partly attributable to cross-reactive neutralising antibodies 50,51 , however, pre-existing T cell responses have also been suggested to reduce the risk of subsequent infection 52 . Supporting a role for de novo or pre-existing T cell responses in early control of SARS-COV-2, we have recently shown that a T cell proliferation signature can be detect prior to PCR positivity in those with mild COVID-19 and this is accompanied by rapid expansion of SARS-CoV-2-specific TCRs 38 . CD4+ T cell responses are more likely to cross-recognise similar viral sequences due to greater flexibility in peptide binding within MHC Class II 53 , in line with the dominance of CD4 responses in ES shown here.…”

“…The latter would be favoured by pre-existing memory T cell responses with the potential to expand rapidly upon cross-recognition of early viral products of SARS-CoV-2 replication. Early T cell proliferation and TCR clonal expansion, even prior to detectable virus, has been observed during mild SARS-CoV-2 22,38 and expansion of virus-specific T cells predates antibody induction after mRNA vaccination 39 . Having found the ES group to be enriched for SARS-CoV-2-specific T cells, particularly against RTC, we therefore investigated the possibility that some of these represented expansions of pre-existing cross-reactive responses.…”

Pre-existing polymerase-specific T cells expand in abortive seronegative SARS-CoV-2

“…The latter would be favoured by pre-existing memory T-cells with the potential to expand rapidly upon cross-recognition of early viral products of SARS-CoV-2 replication. Early T-cell proliferation and T-cell receptor clonal expansion, even prior to detectable virus, has been observed during mild SARS-CoV-2 infection 17,30 and expansion of virus-specific T-cells predates antibody induction after mRNA vaccination 2,31 . Having found the SN-HCW group to be enriched for SARS-CoV-2-specific T-cells, particularly against RTC, we investigated the possibility that some of these represented expansions of pre-existing cross-reactive responses.…”