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Review
. 2020 Aug;41(8):518-530.
doi: 10.1016/j.tips.2020.06.001. Epub 2020 Jun 20.

Deciphering the TCR Repertoire to Solve the COVID-19 Mystery

Lucas Gutierrez  1 , John Beckford  1 , Houda Alachkar  2
Affiliations
Review

Deciphering the TCR Repertoire to Solve the COVID-19 Mystery

Lucas Gutierrez et al. Trends Pharmacol Sci. 2020 Aug.

Abstract

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.

Keywords: COVID-19; SARS-CoV-2; T cell receptors; TCR repertoire; TCR-seq.

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Figures

Figure 1
Figure 1
T Cell-Mediated Response to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection. Infection occurs in the patients after respiratory tract exposure. Subsequently, virus entry occurs via binding to angiotensin-converting enzyme 2 (ACE2) on the surface of various cell types and begins viral replication. Antigen-presenting cells such as dendritic cells endocytose the SARS-CoV-2 virus and degrade them through a process called antigen processing. These antigen fragments are then presented by proteins termed ‘MHC class molecules’, on the cell surface and allow recognition by a T cell. If a CD8+ T cell is capable of binding, it will undergo clonal expansion and directly target infected cells through either perforin/granzymes, FAS ligand/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathways, or secretion of proinflammatory mediators. If the CD4+ T cell is capable of binding, it can activate B cells that recognize the antigen by causing them to clonally proliferate and secrete antibodies to target the SARS-CoV-2 virus. Abbreviations: BCR, B cell receptor; MHC, major histocompatibility complex; TCR, T cell receptor.
Figure 2
Figure 2
Schematic Diagram of the V(D)J Somatic Recombination to Generate T Cell Receptor (TCR). The TCR is composed of the alpha (α) and beta (β) subunit. During T cell development, the loci that encode T cell receptor α and β-chains are rearranged. Variable (V), diversity (D), joining (J), and constant (C) gene segments are represented as blue, red, green, and purple rectangles, respectively. Diversity for the β chain is first created via recombination of D and J segments, followed by the V segments, and finally one of two C segments. Diversity for the α chain is created via recombination of V and J segments, followed by the one C segment. This process also involves the deletion and insertion of nucleotides at the V–D, D–J junctions for the β chain and V–J junctions for the α chain, thus adding more potential diversity to the TCR repertoire.
Figure 3
Figure 3
Workflow for Identifying Public T Cell Receptors (TCRs) Associated with Coronavirus Disease 2019 (COVID-19) to Determine Herd Immunity. (A) Peripheral blood samples collected from COVID-19 infected and healthy uninfected individuals will be the input for the TCR repertoire analyses. Sequences and motif analyses will identify shared TCR clones that are unique to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epitopes. (B) Prediction algorithm generated in (A) should enable the use of TCR sequencing analysis of patient with unknown infection status to determine SARS-CoV-2 exposure history in an individual. This information can be valuable in the fight against COVID-19 as it can be applied to observe the degree of herd immunity in a particular population.
Figure 4
Figure 4
T Cell Receptor (TCR) Repertoire Profiling Workflow in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Studies and Applications. (A) RNA/DNA can be isolated from peripheral blood collected from SARS-CoV-2 infected/vaccinated individuals. (B) Peripheral blood RNA/DNA will be used as an input for TCR sequencing library preparation. (C) TCR sequencing will be done using Illumina or other sequencing platforms and resulting data analyzed using popular bioinformatic tools to characterize the TCR repertoire of SARS-CoV-2 infected/vaccinated individuals. (D) The information obtained can be used to advance immunotherapy development, characterize TCR repertoires in specific populations, and monitor herd immunity.
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