Cross-reactive T cells between SARS-CoV-2 and other human coronaviruses (HCoVs) were identified early on in the pandemic in individuals unexposed to SARS-CoV-2 [16,33,34,41,42,43,44]. The less serious, seasonal HCoVs are the Betacoronavirus OC43 and HKU1 and Alphacoronavirus NL63 and 229E. Approximately 90% of the adult human population has been exposed to each of these viruses, and the four seasonal coronaviruses are responsible for 15–30% of all respiratory tract infections each year, meaning there is a great deal of potential for the pool of memory T cells to cross-react with SARS-CoV-2 [45,46]. Other more serious but less common HCoVs are Middle East respiratory syndrome coronavirus (MERS-CoV) and SARS-CoV-1. These six HCoVs share a degree of amino acid sequence homology with SARS-CoV-2 and, thus, contribute to T cell cross-reactive responses.

The seasonal HCoVs, although prevalent, do not sustain antibodies long-term, and T cell memory responses are present but generally of low magnitude, meaning humans can typically become reinfected within 12 months [47,48]. For SARS-CoV-1, responsible for the 2002–2004 SARS outbreak, memory T cell responses were detectable as long as 17 years after infection, much longer than humoral responses [33]. For MERS-CoV, a similar persistence of T cell responses over humoral responses was observed [49,50,51]. Overall, this highlights the importance of T cell memory and its potential for cross-reactivity among shared epitopes in controlling genetics-related HcoV infections, such as SARS-CoV-2.

SARS-CoV-2-specific T cells have been identified in unexposed individuals, and they are suspected to arise from memory T cell cross-reactivity from previous HcoV infections, which share key T cell epitopes [16,33,34,41,42,43,44,52,53]. A list of SARS-CoV-2 T cell epitopes shown to cross-react with other human coronaviruses is found in Table 1. Cross-reactive T cell responses have been shown to generate functional T cell responses in most but not all reports [12,33,52,54]. However, there remains debate about whether the functionality of these cross-reactive T cells can contribute to the cross-protective effect and impact clinical outcomes.

There is evidence to suggest cross-reactive T cell immunity may not always correlate with positive clinical outcomes. It has been shown that cross-reactive T cells have a low avidity for SARS-CoV-2 homologues, and low avidity T cell responses are correlated with severe COVID-19 [55,56]. This suggests that TCR engagement with peptide-MHC may not be sufficient to properly activate the cross-reactive memory T cells and turn them into robust T effectors against SARS-CoV-2. Also, there is a risk that the cross-reactive T cell repertoire may actually hinder clinical outcomes by engaging only mildly effective effectors against the infection and occupy the immunological space at the expense of more effective, higher affinity/avidity TCR clonotypes [55].

Among adults, cross-reactive T cells against HcoVs are of a low magnitude, and their persistence is not fully understood [48]. Interestingly though, among young adults and children, cross-reactive T cells and antibodies are present, particularly against the spike 2 domain, a region that is relatively conserved between HcoVs [57,58]. Conversely, among the elderly, HcoV-specific T cells and antibodies are mostly non-existent [48]. This may be a contributing factor for why COVID-19 is relatively mild in children and more severe in the elderly.

Despite evidence showing that cross-reactive T cells are less effective in combatting SARS-CoV-2 infection, there is evidence to suggest that cross-reactive T cells can protect from severe COVID-19. In the context of previous recent HcoV infections, the HcoV-specific T cells are able to cross-react and protect against subsequent infection with SARS-CoV-2, which leads to less severe COVID-19 [59]. There may be a time-dependent effect for cross-protection by recent HcoV infection given that seasonal HcoV memory T cells are relatively short-lived. Another study associated protection from COVID-19 with cross-reactive T cells as higher frequencies of cross-reactive memory T cells against SARS-CoV-2 nucleocapsid were present in patients who remained PCR-negative despite exposure to SARS-CoV-2 compared to PCR-positive SARS-CoV-2-exposed individuals [60]. Thus, there is potential for cross-reactive T cells to result in asymptomatic COVID-19.

Another major contributor to HcoV cross-reactivity with SARS-CoV-2 arises from epitopes within the NSPs. Given that the NSPs are relatively well conserved between HcoVs and by harnessing the potential of cross-reactive T cell immunity, the shared homology between NSPs can be utilised for the development of a pan-coronavirus vaccine that has the potential to protect from seasonal HcoVs, SARS-CoV-2 and any future coronaviruses that may arise [61]. There has been much effort to define the cross-reactive epitopes and their associated TCRs that can recognise a broad range of HcoVs and even other zoonotic coronaviruses, which pose a risk to humans [25,56,62,63,64,65,66,67,68,69,70]. Pan-coronavirus vaccines are important for minimising the risk of further pandemics caused by coronaviruses. By utilizing cross-reactive T cell responses driven by non-spike epitopes such as NSPs, such an approach can protect from a variety of HcoVs as well as SARS-CoV-2.

The SARS-CoV-2 spike and nucleocapsid proteins are responsible for a major part of the natural adaptive immune response to SARS-CoV-2, with the spike notably being the antigen used in SARS-CoV-2 vaccines. T cell cross-reactivity to the SARS-CoV-2 spike and nucleocapsid proteins has been implicated in cross-protective immunity. The spike and nucleocapsid epitopes of SARS-CoV-2 share significant homology with other HcoVs. In a humanised mouse model, prior infection with the HcoV OC43 protected mice against disease when infected with SARS-CoV-2. Cross-protection occurred due to CD4+ and CD8+ T cell cross-reactivity to key spike and nucleocapsid epitopes [71]. In humans, a common HLA type, HLA-B*15:01, has been shown to bind SARS-CoV-2 and multiple HcoV epitopes and produce cross-reactive memory T cell responses [72]. This immunodominant, the cross-reactive epitope is likely the reason for the strong association between individuals with HLA-B*15:01 and asymptomatic SARS-CoV-2 infection [73].

There are reports that SARS-CoV-1 and MERS-CoV memory T cells can cross-react with SARS-CoV-2, which is likely due to their close phylogenetic association and high sequence homology [33,74,75]. Both SARS-CoV-1 and MERS-CoV infections result in short-lived B cell and antibody responses but encouragingly long-lasting T cell memory responses up to 18 years post-infection [33,76,77]. However, upon closer inspection, there was low homology between the immunodominant SARS-CoV-2 epitopes and their homologues in SARS-CoV-1 [33,42,78,79]. This may mean that despite the high degree of homology between SARS-CoV-1, MERS-CoV and SARS-CoV-2, as well as the detectable and durable cross-reactive T cell responses already identified in multiple studies, the particular cross-reactive epitopes resulting in an effective immune response against SARS-CoV-2 are not covered by such cross-reactivity. As such, a cross-protective effect arising from such cross-reactivity may be insufficient, although the extent of any cross-protective effect in COVID-19 outcomes requires further research. Given that SARS-CoV-1 was a relatively isolated, historic outbreak from 2002 to 2004, the biological importance holds less relevance in terms of the current public health landscape.

Instances where cross-reactive T cell immunity from HcoVs result in cross-protective effects in SARS-CoV-2 infection are now clearly established in the literature. Further research into the relative contribution of cross-protective versus de novo immunity in combatting COVID-19 would assist in unravelling the often-convoluted history of T cell memory mixed with the somewhat plastic nature of T cell cross-reactivity. In addition, further research is required to address the interplay between cross-reactive T cell immunity and other immune cells to mount an orchestrated immune response against SARS-CoV-2.

2. T Cell Cross-Reactivity between SARS-CoV-2 and Different Vaccines or Pathogens