The Influence of Cross-Reactive T Cells in COVID-19: History
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Contributor:
Peter J. Eggenhuizen
,
Joshua D. Ooi

Memory T cells form from the adaptive immune response to historic infections or vaccinations. Some memory T cells have the potential to recognise unrelated pathogens like severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and generate cross-reactive immune responses. Notably, such T cell cross-reactivity has been observed between SARS-CoV-2 and other human coronaviruses. T cell cross-reactivity has also been observed between SARS-CoV-2 variants from unrelated microbes and unrelated vaccinations against influenza A, tuberculosis and measles, mumps and rubella. 

  • COVID-19
  • SARS-CoV-2
  • Cross-reactive immunity
  • T cell
  • heterologous immunity

1. T cell Cross-Reactivity between SARS-CoV-2 and Other Human Coronaviruses

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 [1][2][3][4][5][6][7]. 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 [8][9]. 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 [10][11]. 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 [2]. For MERS-CoV, a similar persistence of T cell responses over humoral responses was observed [12][13][14]. 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 [1][2][3][4][5][6][7][15][16]. 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 [2][15][17][18]. 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 [19][20]. 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 [19].
Among adults, cross-reactive T cells against HcoVs are of a low magnitude, and their persistence is not fully understood [11]. 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 [21][22]. Conversely, among the elderly, HcoV-specific T cells and antibodies are mostly non-existent [11]. 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 [23]. 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 [24]. 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 [25]. 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 [20][26][27][28][29][30][31][32][33][34][35]. 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 [36]. 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 [37]. 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 [38].
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 [2][39][40]. 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 [2][41][42]. However, upon closer inspection, there was low homology between the immunodominant SARS-CoV-2 epitopes and their homologues in SARS-CoV-1 [2][5][43][44]. 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.
Table 1. SARS-CoV-2 T cell epitopes known to cross-react with human coronavirus epitopes. This list is not exhaustive.
HLA Association SARS-CoV-2 Epitope SARS-CoV-2 Sequence Reference
Cross-reactive Spike Epitopes      
HLA-DP S355–364 RKRISNCVAD [28]
HLA-DR S506–525 QPYRVVVLSFELLHAPATVC [28]
NA S556–564 NKKFLPFQQ [45]
NA S770–777 IAVEQDKN [45]
NA S810–816 KPSKRS [21]
NA S817–824 FIEDLLFN [45]
HLA-DP S816–830 SFIEDLLFNKVTLAD [5][7][20][28]
NA S851–856 CAQKFN [21]
NA S901–906 QMAYRF [21]
HLA-B*15:01 S919–927 NQKLIANQF [38]
HLA-A*02:01 S976–984 VLNDILSRL [46]
NA S997–1002 ITGRLQ [21]
HLA-DP S981–1000 LSRLDKVEAEVQIDRLITGR [28]
NA S1040–1044 VDFCG [21]
NA S1148–1157 FKEELDKYFK [45][47]
NA S1150–1156 EELDKYF [45][47]
NA S1205–1212 KYEQYIKW [21]
NA S1206–1220 YEQYIKWPWYIWLGF [5]
HLA-A*24 S1207–1215 QYIKWPWYI [6]
Cross-reactive
NSP Epitopes		      
HLA-A*02:01 NSP1
(ORF184–92)		 VMVELVAEL [46]
HLA-A*01:01 NSP3
(ORF11637–1646)		 TTDPSFLGRY [6]
HLA-A*02:01 NSP5
(ORF13467–3475)		 VLAWLYAAV [46]
HLA-B*08 NSP5
(ORF13361–3369)		 TPKYKFVRI [6]
HLA-A*02:01 NSP6
(ORF13690–3698)		 KLKDCVMYA [48]
HLA-B*35 NSP736–50 HNDILLAKDTTEAFE [2]
NA NSP726–40 SKLWAQCVQLHNDIL [2]
HLA-A*02:01 NSP8
(ORF14032–4040)		 MLFTMLRKL [46]
NA NSP8
(ORF13976–3990)		 VLKKLKKSLNVAKSE [5]
HLA-B*08 NSP10
(ORF14344–4352)		 DLKGKYVQI [6]
NA NSP12
(ORF15246–5260)		 LMIERFVSLAIDAYP [5]
HLA-A*24 NSP12
(ORF15137–5145)		 FYAYLRKHF [48]
NA NSP12
(ORF15136–5150)		 EFYAYLRKHFSMMIL [5]
NA NSP12
(ORF14966–4980)		 KLLKSIAATRGATVV [5]
HLA-A*02:01 NSP12
(ORF14515–4523)		 TMADLVYAL [46]
NA NSP13
(ORF15881–5895)		 NVNRFNVAITRAKVG [5]
HLA-A*03 NSP13
(ORF15455–5463)		 KLFAAETLK [6]
NA NSP13
(ORF15361–5375)		 TSHKLVLSVNPYVCN [5]
HLA-B*40 NSP14
(ORF16219–6228)		 IEYPIIGDEL [6]
NA NSP15
(ORF16751–6765)		 LDDFVEIIKSQDLSV [6]
NA ORF843–57 SKWYIRVGARKSAPL [6]
NA ORF7a90–104 QEEVQELYSPIFLIV [6]
HLA-B*40 ORF7a40–49 YEGNSPFHPL [6]
HLA-DR ORF626–40 IWNLDYIINLIIKNL [6]
HLA-A*01 ORF620–31 RTFKVSIWNLDY [6]
Cross-reactive Nucleocapsid Epitopes      
HLA-DR N50–64 ASWFTALTQHGKEDL [6]
HLA-B*07 N101–120 MKDLSPRWYFYYLGTGPEAG [2][6]
HLA-B*07:01 N105–113 SPRWYFYYL [26][30][34][48][49]
HLA-DR N127–141 KDGIIWVATEGALNT [6]
NA N221–235 LLLLDRLNQLESKMS [6]
HLA-A*02:01 N221–230 LLLLDRLNQL [48]
HLA-DR N311–325 ASAFFGMSRIGMEVT [6]
NA N326–340 PSGTWLTYTGAIKLD [5]
NA N328–342 GTWLTYTGAIKLDDK [6]                 
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

Given the well-characterised involvement of cross-reactive T cells between HcoVs and SARS-CoV-2 and its variants, other sources of cross-reactivity began to emerge as potentially responsible for cross-reactive T cell immunity to SARS-CoV-2. It was found that HcoVs could not completely explain the cross-reactive memory T cell responses in unexposed individuals to SARS-CoV-2, and, therefore, T cell memory responses from other previous infections or vaccinations also contribute to the cross-reactive T cell response to SARS-CoV-2 [2][5][19][50]. Several notable contributions of memory T cell cross-reactivity between SARS-CoV-2 and the BCG vaccine, influenza A, Measles, Mumps, Rubella vaccine, Paramyxovirus and bacterial pathogens will be explored.

This entry is adapted from the peer-reviewed paper 10.3390/biomedicines12030564

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