Skip to main content
NCBI home page
Elsevier - PMC COVID-19 Collection logoLink to Elsevier - PMC COVID-19 Collection
. 2021 Dec 23;2:6–11. doi: 10.1016/j.clicom.2021.12.001

Altered pre-existing SARS-CoV-2-specific T cell responses in elderly individuals

Naoyuki Taira a, Sakura Toguchi a, Mio Miyagi a, Tomoari Mori b, Hiroaki Tomori c, Koichi Oshiro d, Osamu Tamai e, Mitsuo Kina f, Masatake Miyagi g, Kentaro Tamaki h, Mary K Collins i, Hiroki Ishikawa a,⁎
PMCID: PMC8694817  PMID: 38621014

Abstract

Pre-existing SARS-CoV-2-specific T cells, but not antibodies, have been detected in some unexposed individuals. This may account for some of the diversity in clinical outcomes ranging from asymptomatic infection to severe COVID-19. Although age is a risk factor for COVID-19, how age affects SARS-CoV-2-specific T cell responses remains unknown. We found that pre-existing T cell responses to specific SARS-CoV-2 proteins, Spike (S) and Nucleoprotein (N), were significantly lower in elderly donors (>70 years old) than in young donors. However, substantial pre-existing T cell responses to the viral membrane (M) protein were detected in both young and elderly donors. In contrast, young and elderly donors exhibited comparable T cell responses to S, N, and M proteins after infection with SARS-CoV-2. These data suggest that although SARS-CoV-2 infection can induce T cell responses specific to various viral antigens regardless of age, diversity of target antigen repertoire for long-lived memory T cells specific for SARS-CoV-2 may decline with age; however, memory T cell responses can be maintained by T cells reactive to specific viral proteins such as M. A better understanding of the role of pre-existing SARS-CoV-2-specific T cells that are less susceptible to age-related loss may contribute to development of more effective vaccines for elderly people.

1. Introduction

There is extensive individual variation in severity of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), ranging from asymptomatic infection to fatal pneumonia [1]. Various factors, including age, sex, and comorbidities such as obesity and diabetes, influence the risk of severe COVID-19 [2], [3], [4]. For example, morbidity and mortality among the elderly are significantly higher than among the young [2]. Consideration of protective measures for individuals vulnerable to COVID-19 should be particularly important to control the pandemic [5]. However, cellular and molecular bases of variable risk of COVID-19 disease remain poorly understood.

T cells are assumed to mediate both protective and pathogenic immune responses to SARS-CoV-2 infection [6, 7]. The magnitude and quality of T cell responses induced by SARS-CoV-2 infection are highly heterogeneous and are likely associated with COVID-19 clinical outcomes. For example, SARS-CoV-2-specific T cell numbers and their interferon-γ (IFN-γ) expression in severe COVID-19 patients are lower than in mild COVID-19 patients [8, 9]. Furthermore, asymptomatic COVID-19 patients tend to have increased SARS-CoV-2-specific T cells expressing higher levels of IFN-γ compared to symptomatic patients [10]. This individual variation in T cell responses may be partly explained by heterogeneity in levels of pre-existing SARS-CoV-2-reactive T cells.

Some individuals who have not been exposed to SARS-CoV-2 have nonetheless acquired SARS-CoV-2-reactive T cells, probably through exposure to other common cold coronaviruses [11], [12], [13]. Pre-existing CD4 and CD8 memory T cells, specific to various SARS-CoV-2 proteins, including the structural proteins, Spike (S), Membrane (M), and Nucleoprotein (N), have been detected with significant individual variation, and these pre-existing SARS-CoV-2-reacive T cells are likely associated with immune protection against COVID-19 [14]; however, in other cases, they may exacerbate COVID-19 severity [15, 16]. As many of the current vaccines express the SARS-CoV-2 S protein, only pre-existing S-reactive T cells are activated by these vaccines [17, 18]. Several studies have reported age-related differences in SARS-CoV-2-specific T cell responses in COVID-19 patients [19,20]; however, the effect of age on pre-existing SARS-CoV-2-reactive T cells remains unknown.

In this study, we compared frequencies of T cells reactive to SARS-CoV-2 S, N, and M antigens between young and elderly donors. The relatively elderly Okinawan population, and the moderate rate of SARS-CoV-2 infection in Okinawa, allowed us to examine pre-existing SARS-CoV-2-specific T cells in a cohort of elderly (>70 years old) individuals. We found that pre-existing T cell responses to S and N antigens are significantly impaired in elderly donors compared to young donors, but a proportion of elderly donors exhibit significant, high levels of M-reactive T cell responses. These data provide new insights into age-related alteration of pre-existing SARS-CoV-2-specific T cells.

2. Methods

2.1. Subjects

The study design was approved by the Okinawa Institute of Science and Technology, Graduate University (OIST) human subjects ethics committee (applications HSR-2020–024, HSR-2020–028). All donors provided informed written consent. Young (20 to 50 years of age, n = 66) and elderly volunteers (over 70 years of age, n = 52) were recruited in Okinawa, Japan, between October 2020 and April 2021. 90 unexposed donors (48 young and 42 elderly) had no history of COVID-19, while 28 recovered COVID-19 patients (18 young and 10 elderly) tested positive by PCR for COVID-19 1–3 months before blood collection.

2.2. Peripheral blood mononuclear cells (PBMCs) and plasma isolation

Blood samples were collected in heparin-coated tubes (TERUMO; VP-H100K). PBMCs and plasma were separated using Leucosep tubes pre-filled with Ficoll-Paque Plus (Greiner; 163,288). After adding 5 mL of blood and 3 mL of AIM-V medium (Thermo; 12,055,091), Leucosep tubes were centrifuged at 1000 g at room temperature for 10 min. The white layer containing PBMCs was collected, washed with 10 mL AIM-V medium and centrifuged for 7 min at 600 g, followed by a second washing with centrifugation for 7 min at 400 g. PBMC pellets were resuspended in 500 μL CTL test medium (Cellular Technology Limited (CTL); CTLT-010). Fresh PBMCs were used for IFN-γ ELISpot assays.

2.3. Immunochromatographic SARS-CoV-2 antibody test

Plasma from each donor was first tested using Cellex qSARS-Cov-2 IgG/IgM Cassette Rapid Tests (Cellex 5513C). Plasma from donors who had positive test results in the first test was subsequently retested using SARS-CoV-2 Antibody Detection Kits (KURABO RF-NC001, RF-NC002).

2.4. IFN-γ ELISpot assay

Peptide pools for SARS-CoV-2 S (JPT; PM-WCPV-S-1), N (Miltenyi;130–126–698), and M (Miltenyi;130–126–702) proteins dissolved in DMSO (500 μg/mL for S) or water (50 μg/mL for N and M) were used for cell stimulation. IFN-γ ELISpot assays were performed using Human IFN-γ Single-Color Enzymatic ELISpot kits (CTL; hIFNgp-2 M), according to the manufacturer's instructions. Briefly, freshly isolated PBMCs (1–4 × 105 cells per well) were stimulated with 1 μg/mL peptide solutions for each SARS-CoV-2 protein for 18–20 h. For each sample analysis, negative controls (cells treated with equimolar amounts of DMSO) and positive controls (cells treated with 20 ng/mL phorbol 12-myristate 13-acetate (PMA) and 100 ng/mL ionomycin) were included. After incubation, plates were washed and developed with detection reagents included in the kits. Spots were counted using a CTL ImmunoSpot S6 Analyzer. Antigen-specific spot counts were determined by subtracting background spot counts in a negative control well from wells treated with peptide pools. If >30 spot forming units (SFU)/106 PBMCs in the negative control well or <30 SFU/106 PBMCs in the positive control well were detected, those sample data were excluded from analysis. 26 SFU/106 PBMCs (the mean of negative control SFU + 3 standard deviations) was used as the cut-off for positivity in the ELISpot test.

2.5. Statistical analysis

Mann-Whitney U tests were performed using GraphPad Prism 9.1.0 software. Statistical details are provided in figure legends.

3. Results

3.1. Age-related differences in SARS-CoV-2-specific T cell responses

To assess whether there are age-related differences in SARS-CoV-2-specific T cell responses, we collected peripheral blood from young (20 to 50 years of age) and elderly (>70 years of age), unexposed donors and recovered COVID-19 patients in Okinawa between October 2020 and April 2021. 0% (0/109) of unexposed donors and 53.5% (15/28) of recovered COVID-19 patients were consistently tested positive for anti-SARS-CoV-2 antibodies in two different immunochromatographic tests.

We first compared SARS-CoV-2-specific T cell responses between age groups by Interferon-γ (IFN- γ) ELISpot assays using freshly purified peripheral blood mononuclear cells (PBMCs) stimulated with each of 4 peptide pools covering the major viral structural proteins [N-terminal S (S-1), C-terminal S (S-2), Nucleoprotein (N), or Membrane (M)]. When we tested unexposed individuals with stimulation of S-2 and N peptide pools, we detected IFN-γ spot-forming units (SFU) over a positivity cut-off (26 SFU/106 PBMCs) in a substantial proportion of young, but not elderly donors (13.0% vs 0% for S2 and 36.9% vs 8.8% for N) (Fig. 1 A). Consistent with this, frequencies of S-2- and N-reactive T cells were significantly lower in elderly than in young persons in the unexposed group (Fig. 1A), suggesting age-related defects in acquisition or maintenance of pre-existing memory T cells specific to S-2 and N antigens. However, there was no remarkable difference in the percentages of positive test results for M-specific T cell responses (32.6% vs 35.3%) and the frequency of M-reactive T cells between unexposed young and elderly donors (Fig. 1A). Only a few unexposed donors (4.3% young and 2.9% elderly) tested positive for T cell responses to the S-1 peptide pool (Fig. 1A). PMA and ionomycin stimulation induced comparably high IFN-γ expression in PBMCs from donors who tested positive and negative for T cell responses to SARS-CoV-2 antigens (data not shown).

Fig 1.

Fig 1

Open in a new tab

Altered pre-existing T cell responses to SARS-CoV-2 structural proteins in elderly donors. PBMCs isolated from young (20–50 years of age) and elderly (>70 years of age), unexposed donors (A) and recovered COVID-19 patients (B) were stimulated with peptide pools for SARS-CoV-2 S, N, and M proteins and subjected to IFN-γ ELISpot analysis. Spot-forming units (SFU) representing the frequency of IFN-γ-secreting cells in young unexposed donors (n = 45), young recovered COVID-19 patients (n = 35), elderly unexposed donors (n = 14), and elderly recovered COVID-19 patients (n = 10) are shown. Box-and-whisker plots show quartiles and range. Circle below shows the percentage of donors who tested positive for T cell responses to each peptide pool. Statistical comparisons between age groups utilized the Mann-Whitney test. *p<0.05, ns: not significant.

Consistent with previous studies [11], percentages of positive test results for T cell responses to S, N and M were higher in recovered COVID-19 patients than in unexposed donors (Fig.1B). 58.6% (27 out of 46) of young unexposed donors, 41.1% (14 out of 34) of elderly unexposed donors, 92.3% (12 out of 13) of young recovered COVID-19 patients, and 100% (9 out of 9) of elderly recovered COVID-19 patients tested positive for T cell responses to at least one of the antigens we tested. In contrast to the unexposed group, frequencies of not only M-specific T cells, but also S- and N-specific T cells were comparable between young and elderly donors in the recovered COVID-19 patient group (Fig. 1B).

We next analyzed intraindividual immunodominance of each SARS-CoV-2 antigen in the donors who tested positive for T cell responses to SARS-CoV-2. 33.3% (9 out of 27) of young and 14.2% (2 out of 14) of elderly unexposed donors who tested positive exhibited T cell responses to multiple viral antigens (Fig. 2A). Remarkably, only M-reactive T cells were detected in the majority of elderly unexposed donors who tested positive (Fig. 2A). In contrast, both young and elderly recovered COVID-19 patients who tested positive exhibited mixed T cell responses to multiple viral antigens (Fig. 2B). Taken together, these data suggest that although SARS-CoV-2 infection can induce comparable T cell responses to various viral antigens in both young and elderly individuals, pre-existing memory T cell responses specific to SARS-CoV-2 S and N antigens are impaired in elderly people, while M-specific memory T cell responses are maintained.,

Fig 2.

Fig 2

Open in a new tab

M-specific pre-existing T cell responses predominate in elderly donors. Ratios of spots formed by cells stimulated with SARS-CoV-2 S, N, and M peptide pools in ELISpot data (Fig. 1) were analyzed in unexposed donors (A) and recovered COVID-19 patients (B) donors who tested positive for T cell responses to at least one of the peptide pools.

4. Discussion

Our data indicate that a fraction of elderly donors possess significantly high levels of pre-existing SARS-CoV-2 M-specific T cell responses, though the frequency of pre-existing SARS-CoV-2 S- and N-specific T cells is lower in elderly than young donors. Other recent studies have also reported an age-related decline of S-specific pre-existing CD4 T cells [18, 21]. On the other hand, another study reported that there are no significant differences in the frequency of the pre-existing CD4 and CD8 T cells that are responsive to mixed peptide pools covering S, N, and M proteins between young and elderly donors, although the SARS-CoV-2-responsive naïve CD8 T cells are less numerous in elderly than young [22]. These data suggest that pre-existing T cells specific for SARS-CoV-2 are heterogeneously affected by age in a target antigen-dependent manner and that diversity of the target antigen repertoire for pre-existing T cells may decline with age, but the magnitude of pre-existing T cell responses can be maintained with T cells specific to certain viral proteins, such as M.

As the frequency of pre-existing T cells specific to viral structural proteins S, N, and M is likely associated with protection from SARS-CoV-2 infection [14], focused M-specific T cell responses might be particularly important for protection of elderly individuals who have lower T cell responses to S and N. We speculate that pre-existing M-specific T cells provide protection in SARS-CoV-2 infection by mediating cellular immunity through IFN-γ production and by providing T cell help to S- and N-specific B cells via linked recognition. However, we cannot exclude the possibility that pre-existing M-specific T cells are harmful for some elderly individuals. Several studies suggest that pre-existing SARS-CoV-2-specific T cells are detrimental in COVID-19 [23]. In particular, the frequency of M-specific T cells in COVID-19 patients is thought to be a risk factor, as it is correlated with age and severity of disease [8], although how pre-existing M-specific T cells affect magnitude, kinetics and functions of M-specific T cell responses in COVID-19 patients remains unclear. Thus, both protective and pathogenic functions of pre-existing M-specific T cells can be speculated. A longitudinal comparison of susceptibility and symptom severity of COVID-19 between individuals with and without high pre-existing M-specific T cell responses may provide insights into this issue.

Despite defects in pre-existing T cell responses to S and N, most elderly donors who recovered from mild COVID-19 had abundant T cells specific to S and N antigens at levels comparable to those of young donors, suggesting that elderly individuals can induce T cell responses against S and N antigens upon SARS-CoV-2 infection. However, the relationship between age-related alteration of pre-existing T cells and T cell responses during infection in patients with diverse clinical outcomes of COVID-19 should be investigated in a larger, statistically valid test population. Furthermore, whether diverse SARS-CoV-2-induced T cell clones can mediate long-lasting memory responses and how they are affected by age should be addressed in future studies.

Interestingly, SARS-CoV-1 infection induces long-lasting (>11 years) CD8 memory T cells specific to M141–155 peptide [24]. SARS-CoV-2 M141–155 peptide shows high homology (80% amino acid sequence identity) with SARS-CoV-1 M141–155 peptide and can be targeted by CD4 T cells in convalescent COVID-19 patients [25], suggesting that SARS-CoV-2 M141–155 may also be a potent inducer of long-lasting memory T cells.

What induces pre-existing M-specific T cells? Common cold coronaviruses may induce pre-existing SARS-CoV-2-specific T cell [26, 27]. Amino acid sequence identity between SARS-CoV-2 and other common cold coronaviruses is relatively high for M (NL63: 27.9%, OC43: 38.6%), S-1 (NL63: 14.8%, OC43: 19.8%), S-2 (NL63: 31.8%, OC43: 39.9%), and N (NL63: 25.1%, OC43: 33.0%)[21]. Importantly, several peptides derived from these coronaviruses are cross-reactive with SARS-CoV-2-specific pre-existing T cells [27]. The decrease of memory T cells specific to common cold coronavirus S proteins in elderly donors [21] can account for the decrease of SARS-CoV-2-specific pre-existing T cells. We speculate that memory T cells specific to common cold coronavirus M proteins, which are cross-reactive to SARS-CoV-2 M, might be resistant to age-related decline.

It is worth considering the potential of novel COVID-19 vaccines to induce M-specific immunity. Current vaccine strategies are to induce S-specific antibody and T cell responses [28,29]. Recent studies reported a correlation between the frequency of pre-existing S-specific T cells and vaccine-induced S-specific T cell responses [18], which suggests a role of pre-existing S-specific T cells in cognate T cell help. However, elderly individuals likely would not benefit fully from pre-existing S-specific T cells. To enhance vaccine efficacy among the elderly, it might be reasonable to consider a strategy to induce not only S-specific, but also M-specific immunity, using vaccines based on inactivated viruses or M-fused S antigens. Linked recognition of M-specific T helper cells by S-specific B cells can promote S-specific antibody production by overcoming the defect of cognate T cell help in elderly individuals. Further characterization of M-specific T cells in young and elderly may provide new insights into vaccine-induced immunity that is less affected by age.

Acknowledgements

We thank physicians and nurses at KIN Oncology Clinic for excellent support in collecting blood samples from donors. We also thank Steven Aird for editing the manuscript. We are also grateful to OIST Graduate University for its generous funding of the Immune Signal Unit.

References

  • 1.Merad M., Martin J.C. Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages. Nat. Rev. Immunol. 2020;20:355–362. doi: 10.1038/s41577-020-0353-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.O’Driscoll M., Ribeiro Dos Santos G., Wang L., Cummings D.A.T., Azman A.S., Paireau J., Fontanet A., Cauchemez S., Salje H. Age-specific mortality and immunity patterns of SARS-CoV-2. Nature. 2021;590:140–145. doi: 10.1038/s41586-020-2918-0. [DOI] [PubMed] [Google Scholar]
  • 3.Takahashi T., Ellingson M.K., Wong P., Israelow B., Lucas C., Klein J., Silva J., Mao T., Oh J.E., Tokuyama M., Lu P., Venkataraman A., Park A., Liu F., Meir A., Sun J., Wang E.Y., Casanovas-Massana A., Wyllie A.L., Vogels C.B.F., Earnest R., Lapidus S., Ott I.M., Moore A.J., Shaw A., Fournier J.B., Odio C.D., Farhadian S., Dela Cruz C., Grubaugh N.D., Schulz W.L., Ring A.M., Ko A.I., Omer S.B., Iwasaki A. Sex differences in immune responses that underlie COVID-19 disease outcomes. Nature. 2020;588:315–320. doi: 10.1038/s41586-020-2700-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Stefan N., Birkenfeld A.L., Schulze M.B. Global pandemics interconnected - obesity, impaired metabolic health and COVID-19. Nat. Rev. Endocrinol. 2021;17:135–149. doi: 10.1038/s41574-020-00462-1. [DOI] [PubMed] [Google Scholar]
  • 5.Viana J., Van Dorp C.H., Nunes A., Gomes M.C., Van Boven M., Kretzschmar M.E., Veldhoen M., Rozhnova G. Controlling the pandemic during the SARS-CoV-2 vaccination rollout. Nat. Commun. 2021;12 doi: 10.1038/s41467-021-23938-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Fajgenbaum D.C., June C.H., Storm Cytokine. Cytokine Storm. N. Engl. J. Med. 2020;383:2255–2273. doi: 10.1056/NEJMra2026131. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.De Candia P., Prattichizzo F., Garavelli S., Matarese G., Cells T. T Cells: Warriors of SARS-CoV-2 Infection. Trends Immunol. 2021;42:18–30. doi: 10.1016/j.it.2020.11.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Sattler A., Angermair S., Stockmann H., Heim K.M., Khadzhynov D., Treskatsch S., Halleck F., Kreis M.E., Kotsch K., responses SARS–CoV-2–specific T cell, predisposition correlations with COVID-19 patient. SARS-CoV-2-specific T cell responses and correlations with COVID-19 patient predisposition. J. Clin. Invest. 2020;130:6477–6489. doi: 10.1172/JCI140965. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Chen G., Wu D., Guo W.., Cao Y., Huang D., Wang H., Wang T., Zhang X., Chen H., Yu H., Zhang X., Zhang M., Wu S., Song J., Chen T., Han M., Li S., Luo X., Zhao J., Ning Q. Clinical and immunological features of severe and moderate coronavirus disease 2019. J. Clin. Invest. 2020;130:2620–2629. doi: 10.1172/JCI137244. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Bert N.Le, Clapham H.E., Tan A.T., Chia W.N., Tham C.Y.L., Lim J.M., Kunasegaran K., Tan L.W.L., Dutertre C.A., Shankar N., Lim J.M.E., Sun L.J., Zahari M., Tun Z.M., Kumar V., Lim B.L., Lim S.H., Chia A., Tan Y.J., Tambyah P.A., Kalimuddin S., Lye D., Low J.G.H., Wang L.F., Wan W.Y., Hsu L.Y., Bertoletti A., Tam C.C. Highly functional virus-specific cellular immune response in asymptomatic SARS-CoV-2 infection. J. Exp. Med. 2021;218 doi: 10.1084/jem.20202617. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Braun J., Loyal L., Frentsch M., Wendisch D., Georg P., Kurth F., Hippenstiel S., Dingeldey M., Kruse B., Fauchere F., Baysal E., Mangold M., Henze L., Lauster R., Mall M.A., Beyer K., Rohmel J., Voigt S., Schmitz J., Miltenyi S., Demuth I., Muller M.A., Hocke A., Witzenrath M., Suttorp N., Kern F., Reimer U., Wenschuh H., Drosten C., Corman V.M., Giesecke-Thiel C., Sander L.E., Thiel A. SARS-CoV-2-reactive T cells in healthy donors and patients with COVID-19. Nature. 2020;587:270–274. doi: 10.1038/s41586-020-2598-9. [DOI] [PubMed] [Google Scholar]
  • 12.Bert N.Le, Tan A.T., Kunasegaran K., Tham C.Y.L., Hafezi M., Chia A., Chng M.H.Y., Lin M., Tan N., Linster M., Chia W.N., Chen M.I.C., Wang L.F., Ooi E.E., Kalimuddin S., Tambyah P.A., Low J.G.H., Tan Y.J., Bertoletti A. SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls. Nature. 2020;584:457–462. doi: 10.1038/s41586-020-2550-z. [DOI] [PubMed] [Google Scholar]
  • 13.Woldemeskel B.A., Kwaa A.K., Garliss C.C., Laeyendecker O., Ray S.C., Blankson J.N. Healthy donor T cell responses to common cold coronaviruses and SARS-CoV-2. J. Clin. Invest. 2020;130:6631–6638. doi: 10.1172/JCI143120. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Wyllie D., Jones H.E., Mulchandani R., Trickey A., Taylor-Phillips S., Brooks T., Charlett A., Ades A., Moore P., Boyes J., Hormis A., Todd N., Reckless I., Makin A., Oliver I. SARS-CoV-2 responsive T cell numbers and anti-Spike IgG levels are both associated with protection from COVID-19: A prospective cohort study in keyworkers. Cold Spring Harbor Laboratory; 2020. [Google Scholar]
  • 15.Bacher P., Rosati E., Esser D., Martini G.R., Saggau C., Schiminsky E., Dargvainiene J., Schroder I., Wieters I., Khodamoradi Y., Eberhardt F., Vehreschild M., Neb H., Sonntagbauer M., Conrad C., Tran F., Rosenstiel P., Markewitz R., Wandinger K.P., Augustin M., Rybniker J., Kochanek M., Leypoldt F., Cornely O.A., Koehler P., Franke A., Scheffold A. Low-Avidity CD4+ T Cell Responses to SARS-CoV-2 in Unexposed Individuals and Humans with Severe COVID-19. Immunity. 2020;53:1258–1271. doi: 10.1016/j.immuni.2020.11.016. 1258-1271. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Chen Z., Wherry E.John. T cell responses in patients with COVID-19. Nat. Rev. Immunol. 2020;20:529–536. doi: 10.1038/s41577-020-0402-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Sahin U., Muik A., Derhovanessian E., Vogler I., Kranz L.M., Vormehr M., Baum A., Pascal K., Quandt J., Maurus D., Brachtendorf S., Lörks V., Sikorski J., Hilker R., Becker D., Eller A.K., Grützner J., Boesler C., Rosenbaum C., Kühnle M.C., Luxemburger U., Kemmer-Brück A., Langer D., Bexon M., Bolte S., Karikó K., Palanche T., Fischer B., Schultz A., Shi P.Y., Fontes-Garfias C., Perez J.L., Swanson K.A., Loschko J., Scully I.L., Cutler M., Kalina W., Kyratsous C.A., Cooper D., Dormitzer P.R., Jansen K.U., Türeci Ö. COVID-19 vaccine BNT162b1 elicits human antibody and TH1 T cell responses. Nature. 2020;586:594–599. doi: 10.1038/s41586-020-2814-7. [DOI] [PubMed] [Google Scholar]
  • 18.Loyal L., Braun J., Henze L., Kruse B., Dingeldey M., Reimer U., Kern F., Schwarz T., Mangold M., Unger C., Dörfler F., Kadler S., Rosowski J., Gürcan K., Uyar-Aydin Z., Frentsch M., Kurth F., Schnatbaum K., Eckey M., Hippenstiel S., Hocke A., Müller M.A., Sawitzki B., Miltenyi S., Paul F., Mall M.A., Wenschuh H., Voigt S., Drosten C., Lauster R., Lachman N., Sander L.E., Corman V.M., Röhmel J., Meyer-Arndt L., Thiel A., Giesecke-Thiel C. Cross-reactive CD4+ T cells enhance SARS-CoV-2 immune responses upon infection and vaccination. Science. 2021;374 doi: 10.1126/science.abh1823. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Rydyznski Moderbacher C., Ramirez S.I., Dan J.M., Grifoni A., Hastie K.M., Weiskopf D., Belanger S., Abbott R.K., Kim C., Choi J., Kato Y., Crotty E.G., Kim C., Rawlings S.A., Mateus J., Tse L.P.V., Frazier A., Baric R., Peters B., Greenbaum J., Ollmann Saphire E., Smith D.M., Sette A., Crotty S. Antigen-Specific Adaptive Immunity to SARS-CoV-2 in Acute COVID-19 and Associations with Age and Disease Severity. Cell. 2020;183:996–1012. doi: 10.1016/j.cell.2020.09.038. e1019. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Cohen C.A., Li A.P.Y., Hachim A., Hui D.S.C., Kwan M.Y.W., Tsang O.T.Y., Chiu S.S., Chan W.H., Yau Y.S., Kavian N., Ma F.N.L., Lau E.H.Y., Cheng S.M.S., Poon L.L.M., Peiris M., Valkenburg S.A. SARS-CoV-2 specific T cell responses are lower in children and increase with age and time after infection. Nat. Commun. 2021;12 doi: 10.1038/s41467-021-24938-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Saletti G., Gerlach T., Jansen J.M., Molle A., Elbahesh H., Ludlow M., Li W., Bosch B.J., Osterhaus A.D.M.E., Rimmelzwaan G.F. Older adults lack SARS CoV-2 cross-reactive T lymphocytes directed to human coronaviruses OC43 and NL63. Sci. Rep. 2020;10 doi: 10.1038/s41598-020-78506-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Jo N., Zhang R., Ueno H., Yamamoto T., Weiskopf D., Nagao M., Yamanaka S., Hamazaki Y. Aging and CMV Infection Affect Pre-existing SARS-CoV-2-Reactive CD8+ T Cells in Unexposed Individuals. Front. Aging. 2021;2 doi: 10.3389/fragi.2021.719342. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Thieme C.J., Anft M., Paniskaki K., Blazquez-Navarro A., Doevelaar A., Seibert F.S., Hoelzer B., Konik M.J., Berger M.M., Brenner T., Tempfer C., Watzl C., Meister T.L., Pfaender S., Steinmann E., Dolff S., Dittmer U., Westhoff T.H., Witzke O., Stervbo U., Roch T., Babel N. Robust T Cell Response Toward Spike, Membrane, and Nucleocapsid SARS-CoV-2 Proteins Is Not Associated with Recovery in Critical COVID-19 Patients. Cell Rep. Med. 2020;1 doi: 10.1016/j.xcrm.2020.100092. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Ng O.W., Chia A., Tan A.T., Jadi R.S., Leong H.N., Bertoletti A., Tan Y.J. Memory T cell responses targeting the SARS coronavirus persist up to 11 years post-infection. Vaccine. 2016;34:2008–2014. doi: 10.1016/j.vaccine.2016.02.063. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Keller M.D., Harris K.M., Jensen-Wachspress M.A., Kankate V.V., Lang H., Lazarski C.A., Durkee-Shock J., Lee P.H., Chaudhry K., Webber K., Datar A., Terpilowski M., Reynolds E.K., Stevenson E.M., Val S., Shancer Z., Zhang N., Ulrey R., Ekanem U., Stanojevic M., Geiger A., Liang H., Hoq F., Abraham A.A., Hanley P.J., Cruz C.R., Ferrer K., Dropulic L., Gangler K., Burbelo P.D., Jones R.B., Cohen J.I., Bollard C.M. SARS-CoV-2–specific T cells are rapidly expanded for therapeutic use and target conserved regions of the membrane protein. Blood. 2020;136:2905–2917. doi: 10.1182/blood.2020008488. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Sagar M., Reifler K., Rossi M., Miller N.S., Sinha P., White L.F., Mizgerd J.P. Recent endemic coronavirus infection is associated with less-severe COVID-19. J. Clin. Invest. 2021;131 doi: 10.1172/JCI143380. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Mateus J., Grifoni A., Tarke A., Sidney J., Ramirez S.I., Dan J.M., Burger Z.C., Rawlings S.A., Smith D.M., Phillips E., Mallal S., Lammers M., Rubiro P., Quiambao L., Sutherland A., Yu E.D., Da Silva Antunes R., Greenbaum J., Frazier A., Markmann A.J., Premkumar L., De Silva A., Peters B., Crotty S., Sette A., Weiskopf D. Selective and cross-reactive SARS-CoV-2 T cell epitopes in unexposed humans. Science. 2020;370:89–94. doi: 10.1126/science.abd3871. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Corbett K.S., Edwards D.K., Leist S.R., Abiona O.M., Boyoglu-Barnum S., Gillespie R.A., Himansu S., Schäfer A., Ziwawo C.T., Dipiazza A.T., Dinnon K.H., Elbashir S.M., Shaw C.A., Woods A., Fritch E.J., Martinez D.R., Bock K.W., Minai M., Nagata B.M., Hutchinson G.B., Wu K., Henry C., Bahl K., Garcia-Dominguez D., Ma L., Renzi I., Kong W.P., Schmidt S.D., Wang L., Zhang Y., Phung E., Chang L.A., Loomis R.J., Altaras N.E., Narayanan E., Metkar M., Presnyak V., Liu C., Louder M.K., Shi W., Leung K., Yang E.S., West A., Gully K.L., Stevens L.J., Wang N., Wrapp D., Doria-Rose N.A., Stewart-Jones G., Bennett H., Alvarado G.S., Nason M.C., Ruckwardt T.J., McLellan J.S., Denison M.R., Chappell J.D., Moore I.N., Morabito K.M., Mascola J.R., Baric R.S., Carfi A., Graham B.S. SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness, Nature. 2020;586:567–571. doi: 10.1038/s41586-020-2622-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Polack F.P., Thomas S.J., Kitchin N., Absalon J., Gurtman A., Lockhart S., Perez J.L., Pérez Marc G., Moreira E.D., Zerbini C., Bailey R., Swanson K.A., Roychoudhury S., Koury K., Li P., Kalina W.V., Cooper D., Frenck R.W., Hammitt L.L., Türeci Ö., Nell H., Schaefer A., Ünal S., Tresnan D.B., Mather S., Dormitzer P.R., Şahin U., Jansen K.U., Gruber W.C. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N. Engl. J. Med. 2020;383:2603–2615. doi: 10.1056/NEJMoa2034577. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Clinical Immunology Communications are provided here courtesy of Elsevier

RESOURCES