Deciphering the TCR Repertoire to Solve the COVID-19 Mystery
Authors: Lucas Gutierrez, John Beckford, Houda Alachkar
Journal: Trends in Pharmacological Sciences (2020)

The COVID-19 pandemic revealed vulnerability in elderly population and underscored the role of the aging immune system in the fight against emerging infections.T cells are crucial mediators of antiviral adaptive immunity and delineating the role of the TCR repertoire in the context of SARS-CoV-2 merits research efforts.The TCR repertoire dynamics, composition, and diversity are influenced by several intrinsic and extrinsic factors such as aging, HLA genetic variabilities, viral infection, etc.The architecture of the TCR repertoire largely contributes to the performance of the adaptive immune response against SARS-CoV-2.Advances in sequencing technologies and single-cell immune profiling can be leveraged to monitor adaptive immune responses in COVID-19 patients and guide future SARS-CoV-2 immunotherapy and biomarker development. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected several millions and killed more than quarter of a million worldwide to date. Important questions have remained unanswered: why some patients develop severe disease, while others do not; and what roles do genetic variabilities play in the individual immune response to this viral infection. Here, we discuss the critical role T cells play in the orchestration of the antiviral response underlying the pathogenesis of the disease, COVID-19. We highlight the scientific rationale for comprehensive and longitudinal TCR analyses in COVID-19 and reason that analyzing TCR repertoire in COVID-19 patients would reveal important findings that may explain the outcome disparity observed in these patients. Finally, we provide a framework describing the different strategies, the advantages, and the challenges involved in obtaining useful TCR repertoire data to advance our fight against COVID-19. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected several millions and killed more than quarter of a million worldwide to date. Important questions have remained unanswered: why some patients develop severe disease, while others do not; and what roles do genetic variabilities play in the individual immune response to this viral infection. Here, we discuss the critical role T cells play in the orchestration of the antiviral response underlying the pathogenesis of the disease, COVID-19. We highlight the scientific rationale for comprehensive and longitudinal TCR analyses in COVID-19 and reason that analyzing TCR repertoire in COVID-19 patients would reveal important findings that may explain the outcome disparity observed in these patients. Finally, we provide a framework describing the different strategies, the advantages, and the challenges involved in obtaining useful TCR repertoire data to advance our fight against COVID-19. Since its emergence in December of 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (see Glossary) has infected more than 7 million people and killed more than a quarter million people worldwide. In the US, at least 2 million individuals are confirmed positive for the coronavirus disease 2019 (COVID-19) and the death toll exceeds 100 000 people. The clinical manifestations of patients with SARS-CoV-2 infection range from asymptomatic to mild or severe respiratory symptomatic disease with high viral load [1.Shi Y. et al.COVID-19 infection: the perspectives on immune responses.Cell Death Differ. 2020; 27: 1451-1454Crossref PubMed Scopus (1076) Google Scholar,2.Wang D. et al.Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China.JAMA. 2020; 323: 1061-1069Crossref PubMed Scopus (16387) Google Scholar]. The current coronavirus infects all ages, yet the severity of the disease is different among the age groups. Approximately 15% of the confirmed cases are severe, of whom the majority are either over 65 years of age or patients with underlying medical conditions [3.Grasselli G. et al.Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy region, Italy.JAMA. 2020; 323: 1574-1581Crossref PubMed Scopus (3886) Google Scholar]. As with any virus, the adaptive immune response plays a central role in clearing SARS-CoV-2 infections and directly influences patients' clinical outcome. A proper and specific adaptive immune response can successfully eliminate the virus, which likely occurs in the asymptomatic and mild cases, where having an appropriate genetic background [e.g., human leukocyte antigen (HLA)] that elicits specific antiviral immunity, or boosting the immune responses with therapeutic strategies, may support the development of a protective immune response. However, in severe cases, an impaired immune response leads to the viral infection running unchecked and the highly proliferative virus causing destruction of the infected tissues, particularly in the lungs, where the expression of angiotensin-converting enzyme 2 (ACE2), the receptor required by the virus to enter the cells, is high [4.Tai W. et al.Characterization of the receptor-binding domain (RBD) of 2019 novel coronavirus: implication for development of RBD protein as a viral attachment inhibitor and vaccine.Cell. Mol. 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Several immune characteristics have emerged from early Wuhan cases and were further confirmed in cases in Italy and in New York hospitals, showing that patients with severe infections exhibit increased serum interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and c-reactive protein. In addition, patients with severe disease display high levels of neutrophils combined with a significant decrease in total lymphocytes [7.Wang F. et al.The laboratory tests and host immunity of COVID-19 patients with different severity of illness.JCI Insight. 2020; 5137799Crossref PubMed Scopus (19) Google Scholar]. These proinflammatory immune features were also correlated with disease severity and death [8.Chen G. et al.Clinical and immunological features of severe and moderate coronavirus disease 2019.J. Clin. Invest. 2020; 130: 2620-2629Crossref PubMed Scopus (3389) Google Scholar, 9.Liu F. et al.Prognostic value of interleukin-6, C-reactive protein, and procalcitonin in patients with COVID-19.J. 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Yet, many important questions remained unanswered: why some patients develop severe disease, while others do not; and how genetic variabilities within the immune system impact individual antiviral immune response. Respiratory viruses have evolved in many ways to evade or neutralize innate immunity; therefore, adaptive immunity, which is comprised of B and T cells, must also become activated for proper response. B cells are derived from the bone marrow and produce antibodies that bind to virus particles in the blood and mucosal surfaces, preventing the spread of the infection (humoral mediated antiviral response). Thus, there is an immense research interest in the identification and the use of the antibodies developed against the SARS-CoV-2 as a biomarker for the development of individual immunity or for therapeutic purposes as in the convalescent plasma therapy [12.Shen C. et al.Treatment of 5 critically ill patients with COVID-19 with convalescent plasma.JAMA. 2020; 323: 1582-1589Crossref PubMed Scopus (1733) Google Scholar,13.Duan K. et al.Effectiveness of convalescent plasma therapy in severe COVID-19 patients.Proc. Natl. Acad. Sci. U. S. A. 2020; 117: 9490-9496Crossref PubMed Scopus (1406) Google Scholar]. There are also substantial ongoing efforts placed to develop serological tests to accurately measure the levels of antiviral antibodies in an individual [14.Long Q.X. et al.Antibody responses to SARS-CoV-2 in patients with COVID-19.Nature Medicine. 2020; 26: 845-848Crossref PubMed Scopus (2079) Google Scholar]. This should help the epidemiological assessment of the scale of the viral spread and allow countries to plan for ending lockdowns and the return to normal life. However, current challenges with the sensitivity and specificity for some of these assays are still limiting their wide use. T cells, however, mature in the thymus, and CD8+ T cells kill virus-infected cells (cell-mediated antiviral response) through T cell receptor (TCR)-mediated recognition of viral antigens. Similar to the humoral mediated response, T cells are also essential for antiviral defense. Here, we focus on the role of T cell (cell-mediated) responses and the TCR repertoire, as they are often overlooked in early viral studies. T cells play a crucial role in the immune response to viral infections due to their ability to selectively eliminate virus-infected cells [15.Ranasinghe S. et al.Antiviral CD8(+) T cells restricted by human leukocyte antigen class II exist during natural HIV infection and exhibit clonal expansion.Immunity. 2016; 45: 917-930Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar]. CD8+ T cells recognize viral antigens through their presentation by major histocompatibility class I (MHC I) molecules on virally infected cells as well as on uninfected dendritic cells and macrophages in the lymph nodes (a process known as cross-presentation) (Figure 1) [16.Tang-Huau T.L. et al.Human in vivo-generated monocyte-derived dendritic cells and macrophages cross-present antigens through a vacuolar pathway.Nat. Commun. 2018; 92570Crossref PubMed Scopus (134) Google Scholar]. Once T cells become activated through antigen recognition, they undergo a process termed 'clonal expansion', in which the activated T cell rapidly proliferates to generate a large number of T cells with identical TCRs and thus, identical antigen recognition [17.Huang H. et al.Select sequencing of clonally expanded CD8(+) T cells reveals limits to clonal expansion.Proc. Natl. Acad. Sci. U. S. A. 2019; 116: 8995-9001Crossref PubMed Scopus (55) Google Scholar]. To eliminate virus-infected cells, expanded CD8+ T cell clones, with TCRs specific for viral antigens, directly lyse them by perforin/granzyme release, induce apoptosis through tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or Fas ligand, and secrete proinflammatory mediators such as interferon-γ (IFN-γ) [18.Braciale T.J. et al.Regulating the adaptive immune response to respiratory virus infection.Nat. Rev. Immunol. 2012; 12: 295-305Crossref PubMed Scopus (276) Google Scholar] (Figure 1). T cells are crucial mediators of antiviral adaptive immunity and delineating the role of the TCR in the context of SARS-CoV-2 should garner vast interest. The specificity of T cells toward viral antigens presented by all nucleated cells on MHCs is determined by their TCR [19.Song I. et al.Broad TCR repertoire and diverse structural solutions for recognition of an immunodominant CD8(+) T cell epitope.Nat. Struct. Mol. Biol. 2017; 24: 395-406Crossref PubMed Scopus (64) Google Scholar, 20.Hansen T.H. Bouvier M. MHC class I antigen presentation: learning from viral evasion strategies.Nat. Rev. Immunol. 2009; 9: 503-513Crossref PubMed Scopus (301) Google Scholar, 21.Stumptner-Cuvelette P. et al.HIV-1 Nef impairs MHC class II antigen presentation and surface expression.Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 12144-12149Crossref PubMed Scopus (213) Google Scholar]. Roughly 95% of the TCRs on circulating T cells are alpha (α) and beta (β) subunit heterodimers. TCR specificity for any given antigen is shaped through V(D)J recombination (rearrangement) [22.Dash P. et al.Quantifiable predictive features define epitope-specific T cell receptor repertoires.Nature. 2017; 547: 89-93Crossref PubMed Scopus (502) Google Scholar]. During recombination, V and J (TCR alpha) or V, D, and J (TCR beta) gene segments are randomly selected from an array of V and J exons [23.Bassing C.H. et al.The mechanism and regulation of chromosomal V(D)J recombination.Cell. 2002; 109: S45-S55Abstract Full Text Full Text PDF PubMed Scopus (726) Google Scholar]. They undergo random addition and deletion of nucleotides to form the final mature TCR gene [24.Komori T. et al.Lack of N regions in antigen receptor variable region genes of TdT-deficient lymphocytes.Science. 1993; 261: 1171-1175Crossref PubMed Scopus (415) Google Scholar] (Figure 2). This process can generate up to 1015 unique TCRs [25.Nikolich-Zugich J. et al.The many important facets of T-cell repertoire diversity.Nat. Rev. Immunol. 2004; 4: 123-132Crossref PubMed Scopus (496) Google Scholar,26.Laydon D.J. et al.Estimating T-cell repertoire diversity: limitations of classical estimators and a new approach.Philos. Trans. R. Soc. Lond. Ser. B Biol. Sci. 2015; 37020140291Crossref PubMed Scopus (131) Google Scholar]. The antigen specificity of each TCR lies in its complementarity-determining region 3 (CDR3), which is located at the V(D)J junction. As a result, each unique T cell clone is identified by its unique CDR3 region and, therefore, unique antigen specificity. The TCR recombination process generates a diverse TCR repertoire capable of recognizing a wide range of antigens and providing potent antiviral immunity [27.Jorgensen J.L. et al.Mapping T-cell receptor-peptide contacts by variant peptide immunization of single-chain transgenics.Nature. 1992; 355: 224-230Crossref PubMed Scopus (533) Google Scholar]. The diversity and the composition of the TCR repertoire changes in response to acute and chronic infection, aging, cancer, and many other external and internal forces, making the repertoire highly dynamic. Exposure to antigen triggers massive expansion of T cells capable of recognizing the particular antigen (antigen-specific T cells), leading to skewing of the TCR repertoire (TCR bias) to favor antigen-specific T cells [28.Chen G. et al.Sequence and structural analyses reveal distinct and highly diverse human CD8(+) TCR repertoires to immunodominant viral antigens.Cell Rep. 2017; 19: 569-583Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar, 29.Trautmann L. et al.Selection of T cell clones expressing high-affinity public TCRs within human cytomegalovirus-specific CD8 T cell responses.J. Immunol. 2005; 175: 6123-6132Crossref PubMed Scopus (193) Google Scholar, 30.Pantaleo G. et al.Major expansion of CD8+ T cells with a predominant V beta usage during the primary immune response to HIV.Nature. 1994; 370: 463-467Crossref PubMed Scopus (565) Google Scholar]. Evidence for TCR bias in antiviral immunity is demonstrated for many viral infections, such as the Epstein-Barr virus (EBV) and influenza. TCR analysis of peripheral blood lymphocytes from either EBV-positive or influenza-positive individuals has revealed several T cell clonotypes with recurrent TCR motifs shared by individuals [31.Callan M.F. et al.T cell selection during the evolution of CD8+ T cell memory in vivo.Eur. J. Immunol. 1998; 28: 4382-4390Crossref PubMed Google Scholar, 32.Sant S. et al.Single-cell approach to influenza-specific CD8(+) T cell receptor repertoires across different age groups, tissues, and following influenza virus infection.Front. Immunol. 2018; 9: 1453Crossref PubMed Scopus (52) Google Scholar, 33.Gil A. et al.Epstein-Barr virus epitope-major histocompatibility complex interaction combined with convergent recombination drives selection of diverse T cell receptor alpha and beta repertoires.mBio. 2020; 11e00250-20Crossref PubMed Scopus (14) Google Scholar]. In addition, the expansion and maintenance of TCRs during chronic cytomegalovirus (CMV) infection demonstrates the dynamic and evolving nature of the TCR repertoire in response to viral infection [34.Schober K. et al.Reverse TCR repertoire evolution toward dominant low-affinity clones during chronic CMV infection.Nat. Immunol. 2020; 21: 434-441Crossref PubMed Scopus (67) Google Scholar]. Therefore, it stands to reason that the presence of a bias exists in the TCR repertoire as a result of the SARS-CoV-2 infection. The characteristics of the TCR repertoire, such as diversity, composition, and dynamics, are controlled by both genetic and epigenetic factors, leading to interindividual variability. Here we discuss two factors that we believe are relevant to COVID-19 and the observed immune response disparities among patients. It is well known that TCR repertoire diversity declines with aging. This decrease in TCR diversity as we age has also been demonstrated in various studies using high-throughput sequencing [TCR sequencing (TCR-seq)] technology. One study estimated the TCRβ diversity in naïve T cell repertoires was 60–120 million for individuals in the first two decades of life and declined to 8–57 million in individuals over 70 years old [35.Britanova O.V. et al.Dynamics of individual T cell repertoires: from cord blood to centenarians.J. Immunol. 2016; 196: 5005-5013Crossref PubMed Scopus (105) Google Scholar]. The evidence of aging TCR repertoire is demonstrated in the antiviral response against the human influenza A virus [39.Nguyen T.H.O. et al.Perturbed CD8(+) T cell immunity across universal influenza epitopes in the elderly.J. Leukoc. Biol. 2018; 103: 321-339Crossref PubMed Scopus (48) Google Scholar,40.Gil A. et al.Narrowing of human influenza A virus-specific T cell receptor alpha and beta repertoires with increasing age.J. Virol. 2015; 89: 4102-4116Crossref PubMed Scopus (59) Google Scholar]. This may be of particular interest in the context of COVID-19, considering that the mortality of elderly patients with COVID-19 is higher than that of young and middle-aged patients [3.Grasselli G. et al.Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy region, Italy.JAMA. 2020; 323: 1574-1581Crossref PubMed Scopus (3886) Google Scholar,36.Wu Z. McGoogan J.M. 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Genetic differences in the HLA genes are well known to influence the composition of TCR repertoire by affecting intra- and extrathymic clonal selection, partially accounting for individual variations in the immune response to pathogens [41.Sharon E. et al.Genetic variation in MHC proteins is associated with T cell receptor expression biases.Nat. Genet. 2016; 48: 995-1002Crossref PubMed Scopus (102) Google Scholar, 42.Akolkar P.N. et al.Influence of HLA genes on T cell receptor V segment frequencies and expression levels in peripheral blood lymphocytes.J. Immunol. 1993; 150: 2761-2773PubMed Google Scholar, 43.Reed E.F. et al.Influence of HLA class I and class II antigens on the peripheral T-cell receptor repertoire.Hum. Immunol. 1994; 40: 111-122Crossref PubMed Scopus (17) Google Scholar]. These genetic differences in the HLA genes directly affect the binding affinity of MHC I/II molecules to antigens and, consequently, influence T cell recognition of pathogen-derived antigens [44.Kekik C. et al.Relationship between HLA tissue type, CMV infection, and acute graft-vs-host disease after allogeneic hematopoietic stem cell transplantation: single-center experience.Transplant. Proc. 2009; 41: 3859-3862Crossref PubMed Scopus (15) Google Scholar, 45.Quinones-Parra S. et al.Preexisting CD8+ T-cell immunity to the H7N9 influenza A virus varies across ethnicities.Proc. Natl. Acad. Sci. U. S. 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Virol. 2020; (Published online April 17, 2020. https://doi.org/10.1128/JVI.00510-20)Crossref Scopus (339) Google Scholar]. The same allele was previously associated with susceptibility to SARS [49.Lin M. et al.Association of HLA class I with severe acute respiratory syndrome coronavirus infection.BMC Med. Genet. 2003; 49Crossref PubMed Scopus (253) Google Scholar]. In contrast, HLA-B*15:03 was found to have the greatest capacity to present highly conserved SARS-CoV-2 peptides that are shared among common human coronaviruses, suggesting a potential cross-protective T cell immunity [48.Nguyen A. et al.Human leukocyte antigen susceptibility map for SARS-CoV-2.J. Virol. 2020; (Published online April 17, 2020. https://doi.org/10.1128/JVI.00510-20)Crossref Scopus (339) Google Scholar]. These observations raise the important question of which alleles confer susceptibility or resistance to the SARS-CoV-2 infection. A protective T cell-driven immune response to unpredicted antigens requires the immune system to generate a diverse TCR repertoire that is ready for any novel pathogen/antigen challenge, such as SARS-CoV-2. Therefore, the size and the diversity of the TCR repertoire are major determinants of the immune response to a given antigen [50.Ritmahan W. et al.Revealing factors determining immunodominant responses against dominant epitopes.Immunogenetics. 2020; 72: 109-118Crossref PubMed Scopus (17) Google Scholar]. The TCR repertoire can be further divided into naive and memory. The naive TCR repertoire represents the repertoire of antigen-inexperienced T cells. This population is shaped by thymopoiesis, which introduces new T cell clones and, therefore, new antigen specificities, to diversify the TCR repertoire [51.Kumar B.V. et al.Human T cell development, localization, and function throughout life.Immunity. 2018; 48: 202-213Abstract Full Text Full Text PDF PubMed Scopus (688) Google Scholar]. Thymopoiesis can generate SAR-CoV-2 reactive T cells where they have not existed previously. The memory TCR repertoire represents the repertoire of antigen-experienced T cells. It is shaped by an individual's history of antigen exposure, whereby those T cells that have participated in immune responses persist long term. Memory T cells, though they have been selected for by different antigens, such as those generated against prior coronaviruses, may still generate responses against novel viruses such as the SARS-CoV-2 [52.Riley T.P. et al.T cell receptor cross-reactivity expanded by dramatic peptide-MHC adaptability.Nat. Chem. Biol. 2018; 14: 934-942Crossref PubMed Scopus (64) Google Scholar]. Indeed, a recent study reported that T cell reactivity to SARS-CoV-2 epitopes is also detected in nonexposed individuals, suggesting crossreactive T cell recognition between circulating 'common cold' coronaviruses and SARS-CoV-2 [53.Grifoni A. et al.Targets of T cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals.Cell. 2020; 181: 1489-1501.e15Abstract Full Text Full Text PDF PubMed Scopus (2561) Google Scholar]. The development of faster and cheaper sequencing technologies, augmented by the advances in computational tools, support the feasibility of using TCR analyses not only to track SARS-CoV-2-specific T cell expansion post-COVID-19 infection or in the course of treating patients with COVID-19, but also to establish certain features of the TCR repertoire architecture as predictive biomarkers for patients' clinical outcome. A recent study demonstrated the feasibility and value of these analyses in patients with COVID-19. In ten patients with either early recovery stage or late recovery stage COVID-19 and five healthy donors, TCR-seq analysis showed that T cell expansion was lower in the early recovery group than in the healthy control group. Also, the naïve or central memory T cells showed little clonal expansion, while effector memory T cells, terminal effector CD8+ T cells, and proliferating T cells showed higher expansion levels. The study found that the most highly expanded clone in the early recovered group was TRAV8-6-TRAJ45:TRAV7-8-TRBJ2-1 [54.Wen W. et al.Immune cell profiling of COVID-19 patients in the recovery stage by single-cell sequencing.Cell Discov. 2020; 6: 31Crossref PubMed Scopus (533) Google Scholar]. Thus, a comprehensive characterization of the dynamics and composition of the TCR repertoires to SARS-CoV-2 infection can largely contribute to the evolving understanding of the functional and mechanistic involvement of the adaptive immune cell response and potentially guide the design of effective treatment. Here we summarize some of the most relevant clinical applications of obtaining comprehensive TCR repertoire data in the setting of COVID-19. Recent efforts have focused on identifying shared motifs in core sequences to predict conserved residues driving essential elements of TCR recognition [22.Dash P. et al.Quantifiable predictive features define epitope-specific T cell receptor repertoires.Nature. 2017; 547: 89-93Crossref PubMed Scopus (502) Google Scholar,55.Glanville J. et al.Identifying specificity groups in the T cell receptor repertoire.Nature. 2017; 547: 94-98Crossref PubMed Scopus (609) Google Scholar]. As with any other viral infection, the ability of individuals' TCR repertoire to effectively clear SARS-CoV-2 infection is highly dependent on its composition. Epitope-specific T cells have been identified in a study using samples obtained from individuals previously infected with SARS-CoV [56.Liu J. et al.The membrane protein of severe acute respiratory syndrome coronavirus acts as a dominant immunogen revealed by a clustering region of novel functionally and structurally defined cytotoxic T-lymphocyte epitopes.J. Infect. Dis. 2010; 202: 1171-1180Crossref PubMed Scopus (106) Google Scholar]. Similarly, another study demonstrated the presence of epitope-specific public T cells in both healthy and influenza-infected patients [32.Sant S. et al.Single-cell approach to influenza-specific CD8(+) T cell receptor repertoires across different age groups, tissues, and following influenza virus infection.Front. Immunol. 2018; 9: 1453Crossref PubMed Scopus (52) Google Scholar]. These studies show a correlation between the presence of specific T cell clones and antiviral immunity. Beyond identifying specific clones, TCRβ profiling has demonstrated convergent TCRβ repertoire evolution in large cohorts of unrelated individuals infected with CMV or vaccinated against yellow fever [57.Emerson R.O. et al.Immunosequencing identifies signatures of cytomegalovirus exposure history and HLA-mediated effects on the T cell repertoire.Nat. Genet. 2017; 49: 659-665Crossref PubMed Scopus (288) Google Scholar,58.Pogorelyy M.V. et al.Precise tracking of vaccine-responding T cell clones reveals convergent and personalized response in identical twins.Proc. Natl. Acad. Sci. U. S. A. 2018; 115: 12704-12709Crossref PubMed Scopus (72) Google Scholar]. Additional work has demonstrated that information obtained from public TCRs in smallpox vaccinated mice can be used to identify smallpox vaccinated mice with >99% accuracy [59.Wolf K. et al.Identifying and tracking low-frequency vir