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 Role of T Cells in the Immune Response against SARS-CoV-2
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. There are also substantial ongoing efforts placed to develop serological tests to accurately measure the levels of antiviral antibodies in an individual. 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 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).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.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). 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.
TCR-Based Immunotherapy for COVID-19
Adoptive transfer of TCR engineered T cell (TCR-T) has been applied to treat viral infections such as hepatitis B and C. This was also demonstrated in preclinical models for prior coronaviruses such as SARS; engineered SARS-CoV-specific TCR-T cells from normal individuals have demonstrated antiviral activity that was comparable with that of natural SARS-CoV-specific memory CD8+ T cells. The ability to identify potential TCR clones that are specific to SARS-CoV-2 antigens can be leveraged in the development of highly specific and advanced forms of immunotherapy based on TCR structural and sequence information. Identification of public clones through TCR repertoire profiling in infected and vaccinated individuals may guide the design of future TCR-T immunotherapies against SARS-CoV-2. SARS-CoV-2 reactive T cells can be expanded ex vivo and infused directly into an individual to shorten recovery time and increase the magnitude of response.
Recent advances in TCR-seq have provided evidence for a close relationship between TCR diversity and immune responses against viral antigens. Under homeostatic conditions, the TCR repertoire is largely diverse and polyclonal. However, in the context of viral infection, preferential selection of T cell clones can contribute to the narrowing of an antigen-selected TCR repertoire. To what extent SARS-CoV-2 influences the TCR repertoire remains to be assessed. In addition, what impact the COVID-19 resulting lymphocytopenia has on the TCR repertoire architecture, diversity, and composition, and how comorbidities such as diabetes, obesity, and hypertension which are implicated in COVID-19 severity may influence the TCR repertoire, are questions that warrant attention.
Studying the TCR repertoire may also reveal potential public TCRs, which may allow us to track infection as well as understand immunity against this infection. In line with our opinion, several efforts are on the way to perform TCR analysis in COVID-19 patients. A recent study has reported a longitudinal high-throughput TCR-seq to track changes in the T cell repertoire following two mild cases of COVID-19 infection. In addition, clinical trials (clinical trial numbers: NCT04379466 and NCT04362865) have been initiated to examine the immune repertoire in COVID-19 patients. The NCT04362865 trial, sponsored by the National Institute of Health, is particularly interesting as it aims to investigate both the B and T cell repertoire and immune response in patients with acute and resolved COVID-19 infection. We should emphasize that the B cell immunoglobulin repertoire analysis is also a significant and urgently needed task. Indeed, a recent study has applied a single-cell immune profiling approach that combines single-cell transcriptomic analysis with single-cell TCR and B cell receptor (BCR) sequencing technologies to examine the cellular context of the adaptive immune response and immune repertoires of T and B cells in blood samples of COVID-19 patients
We foresee that other platforms can also provide valuable data, such as CyTOF mass cytometry and the 10×Genomics immune profiling platform that utilizes DNA-barcoded peptide-MHC (pMHC) multimers and antibodies conjugated to barcodes to dissect the immune repertoire in the setting of COVID-19. These analyses should reveal clonality, diversity, antigen specificity, and cellular context; and pair α and β chain TCR sequences from individual T cells. It also allows for pairing heavy and light chain immunoglobulin sequences from individual B cells. These data, combined with sophisticated computational methods, will enable the identification of the paired TCR α and β chain sequences with TCR-pMHC specificity corresponding to SARS-CoV-2. More importantly it will simultaneously measure cell surface protein expression with gene expression and uncover meaningful details related to the mechanisms contributing to the pathology of this infection and the patient’s clinical outcome.
Together, these technologies can be leveraged to monitor adaptive immune responses in COVID-19 patients and guide future SARS-CoV-2 immunotherapy development. Which characteristics of the TCR repertoire may explain the disproportional risk of COVID-19 in older population and how genetic diversity in the HLAs contribute to the SARS-CoV-2-specific TCR repertoire and potentially the immune response are some of many outstanding questions to be tackled
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