Cross-reactive CD4⁺ T cells enhance SARS-CoV-2 immune responses upon infection and vaccination

Abstract

While evidence for pre-existing SARS-CoV-2-cross-reactive CD4+ T cells in unexposed individuals is increasing, their functional significance remains unclear. Here, we comprehensively determined SARS-CoV-2-cross-reactivity and human coronavirus-reactivity in unexposed individuals. SARS-CoV-2-cross-reactive CD4+ T cells were ubiquitous, but their presence decreased with age. Within the spike glycoprotein fusion domain, we identified a universal immunodominant coronavirus-specific peptide epitope (iCope). Pre-existing spike- and iCope-reactive memory T cells were efficiently recruited into mild SARS-CoV-2 infections and their abundance correlated with higher IgG titers. Importantly, the cells were also reactivated after primary BNT162b2 COVID-19 mRNA vaccination in which their kinetics resembled that of secondary immune responses. Our results highlight the functional importance of pre-existing spike-cross-reactive T cells in SARS-CoV-2 infection and vaccination. Abundant spike-specific cross-immunity may be responsible for the unexpectedly high efficacy of current vaccines even with single doses and the high rate of asymptomatic/mild infection courses.

T cell immunity to SARS-CoV-2

“…Since the outbreak of COVID-19, multiple studies have detected T cell responses in the peripheral blood of unexposed individuals that cross-recognize several structural and non-structural SARS-CoV-2 proteins [ 17 , 23 , 40 , 43 , 44 , [62] , [63] , [64] , [65] , [66] , [67] , [68] ]. Cross-reactive SARS-CoV-2-specific memory CD4 + T cells are readily detectable ex vivo in approximately 20–50% of unexposed people and detectable in almost all individuals after in vitro expansion [ 62 ], whereas cross-reactive SARS-CoV-2-specific memory CD8 + T cells are less commonly detected in peripheral blood [ 40 ].…”

“…Given their sequence homology, it has been proposed that previous infections with endemic common cold human coronaviruses (HCoVs) such as HCoV-OC43, HCoV-229E, HCoV-HKU1, and HCoV-NL63 induce SARS-CoV-2-cross-reactive T cell immunity. Indeed, expanded HCoV-specific CD4 + and CD8 + T cells from unexposed donors show some level of reactivity to SARS-CoV-2 antigens and vice versa [ 43 , 62 , 64 , [66] , [67] , [68] , [69] ], and shared clonotypes can be detected between HCoV- and SARS-CoV-2-specific T cells in uninfected individuals [ 66 , 68 , 69 ]. These cross-reactive CD4 + and CD8 + T cell are generally directed against highly conserved epitopes among coronaviruses [ [66] , [67] , [68] , 70 ], further supporting the concept that SARS-CoV-2-cross-reactive-T cell responses are preferentially mediated by HCoVs.…”

“…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 ]. A similar effect can be seen after mRNA COVID-19 vaccination, where increased spike-specific CD4 + T cell and antibody responses are observed in individuals with detectable pre-existing CD4 + T cell responses ex vivo [ 67 , 77 ].…”

Durability of ChAdOx1 nCov-19 (AZD1222) vaccination in people living with HIV - responses to SARS-CoV-2, variants of concern and circulating coronaviruses

“…Pre-existing cross-reactive T and B cell responses in individuals naïve to SARS-CoV-2 infection and vaccination to the circulating common cold coronaviruses (CCC) HKU1, OC43, 299E and NL63 have been identified (28)(29)(30)(31)(32)(33)(34), however the impact of this cross-reactivity is unclear. While some reports point to a beneficial role in mitigating disease severity and the induction of neutralising antibodies in both vaccination and natural infection (33,35,36), others report no biological function (37,38) or a potential pathological role (39).…”

Analysis of the Immunogenicity of mRNA-1273 SARS-CoV-2 Vaccine in Breast Cancer Patients Treated With Cyclin-Dependent Kinases 4 and 6 Inhibitors (CDKi): Limited T-Cell Immunity Despite Satisfactory Humoral Response.

“…On the other hand, we do not include neutralizing antibodies evaluation that could be responsible of protection even with lack of adequate T-cell response and they have been correlated with speci c antibodies [10]. Also, we include patients with cross-reactive cellular immunity at baseline that could have improved the nal rate of T-cell response [18,19].…”