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Since the helper T-cell bonds with specific antigen presented by dendritic cell and that same helper T-cell also activates B-cell by bonding with antigen presented by B-cell, it made me think that the antigens presented by both of them should be same. If that specificity is true, then what's the difference between an antibody and T-cell receptor? Because both T-cell receptor and Antibody are specific to an antigen.
B cell receptors (BCR) work on a similar paradigm, but a different mechanism than the TCR completely, structure aside. When a B cell encounters an antigen that binds to it's BCR, the receptor-antigen complex is internalized where it's processed onto class-II MHC.
Source: UP Manila Lecture, Marilen Parungao (link)
The peptides have to be processed to ~22-residue fragments to load on MHC-II, and the whole antigen is thus fragmented on the extrinsic processing pathway. To be specific, one antigen becomes many different peptides on many different MHC-II on the same B cell. You can imagine this produces some diversity among peptides suitable that at least one Th cell with similar specificity might bind. Class switching and somatic hypermutation that the B cells undergo help them attain greater utility and specificity, and the membrane-bound BCR is alternatively processed so that the c-terminus domain traffics antibodies to be secreted (2).
On the other hand, the TCR is specific with a little wiggle room to a particular MHC-I or II loaded peptide, with the exception of yδ T cells which have been shown to be largely MHC-independent (3). The same situation follows, however, that your antigen presenting cell or APC has many different peptides of the same antigen loaded on MHC, just as cells expressing MHC-I might, which means that the T cells are also not recognizing the same exact peptide sequence. Since they originate from the same antigen, however, your cytotoxic and helper T cells can be specific for the same "target."
Mini-review: An overview of T cell receptors
Click through and see at a glance the key markers for immune cell phenotyping and for identifying specific stages of apoptosis.
Human and mouse immune cell marker databases. All the facts at your fingertips from cell lineage to marker proteins, discover for yourself.
The immune system has a near limitless capacity for detecting abnormalities. This remarkable ability for selfinterrogation is achieved by the related structures of two molecules, immunoglobulins and T cell receptors (TCR). The TCR, a defining structure of T cells, is a transmembrane heterodimer consisting of either an alpha and beta chain or delta and gamma chain linked by a disulphide bond. Within these chains are complementary determining regions (CDRs) which determine the antigen to which the TCR will bind. TCRs activate the T cells in which they reside leading to a plethora of immune responses. Harnessing the power of this response and of TCR specificity is leading to a new generation of extremely promising immunotherapies.
An Overview of T Cell Receptors Mini-review
What is an Antigen
An antigen is any substance that triggers an immune response in the body. Antigens are also called immunogens. Antigenic determinants are present on the surface of the antigen and these antigenic determinants fit with the receptor molecules with a complementary structure. These receptor molecules are present on the T and B lymphocytes in the blood. The binding of the antigenic determinant to the corresponding receptor on the lymphocyte stimulate the proliferation of that particular lymphocyte type bearing the complementary receptor. The proliferation of the lymphocyte initiates the immune response and produces specific antibodies to that particular antigen determinant. It also activates cytotoxic T cells. Different types of antigens bind to the different receptors of the lymphocytes as shown in figure 1.
Figure 1: Receptor Specificity of Lymphocytes
Antigens can be divided into various types based on their origin. Exogenous antigens are the substances that enter the body from the external environment. Pathogens such as bacteria, virus, fungi, and parasites are examples of exogenous antigens. In addition, snake venom, toxins, red blood cell antigens, and antigens in the serum are also exogenous antigens. The entrance of exogenous antigens can occur through ingestion, respiration, injections or through wounds. Endogenous antigens are the metabolic products of the microorganisms living in the body. Autoantigens are the components of the body that are recognized as antigens by the immune system. The recognition of autoantigens causes autoimmune diseases. Neoantigens are the T-cell antigens present on the surface of cells infected by oncogenic viruses.
What is an Antibody
An antibody is a glycoprotein produced in the blood by plasma cells in response to a particular antigen. Antibodies are also called immunoglobulins (Ig). An antibody is made up of four peptide chains, two heavy chains and two light chains. The complete molecule is Y-shaped. The antigen binding sites are present at the each end of the two light chains. It is a variable region of amino acids, which gives specificity to the antigen binding. The size of the antigen binding site is 110-130 amino acids. Five types of antigens can be identifies based on the structure and the function of the constant region. They are IgM, IgG, IgE, IgD, and IgA. The structure of an antibody is shown in figure 2.
Figure 2: Antibody Structure
Antibodies can be found in both blood circulation and the lymphatic system. The attachment of antibodies to their specific antigens neutralizes the antigen and triggers an immune response. This binding can immobilize pathogens from the circulation. It also induces the complement reactions, which lyse the pathogen. The complement reactions can attract the phagocytes as well.
T Cell Differentiation
T cells (T lymphocytes) derive their names from the organs in which they develop in the thymus. They arise in the bone marrow but migrate to the thymus gland to mature.The diverse responses of T cells are collectively called cell-mediated immune reactions. This is to distinguish them from antibody responses, which, of course, also depend on cells (B cells). T cells cannot recognize antigen alone, as for T cell receptors (TCRs), they can recognize only antigen bound to cell-membrane proteins (MHC molecules). TCRs have different structures thus they bind to different molecular structures and have different genetic codes. Like antibody responses, T cell responses are exquisitely antigen-specific, and they are at least as important as antibodies in defending vertebrates against infection. Indeed, most adaptive immune responses, including antibody responses, require helper T cells for their initiation. Most importantly, unlike B cells, T cells can help eliminate pathogens that reside inside host cells.
Types of T Cells
According to the function and surface marker, T cells can be divided into four main classes.
- Cytotoxic T cells directly kill infected cells by inducing them to undergo apoptosis, these cells like a "killer" or cytotoxin because they kill cells of interest that produce a particular antigen. The major surface marker of cytotoxic T cells is CD8, also known as killer T cells.
- Helper T cells play an intermediate role in the immune response. They proliferate to activate B cells to make antibody responses and macrophages to destroy microorganisms that either invaded the macrophage were ingested by it. Helper T cells also help activate cytotoxic T cells to kill infected target cells. Helper T cells themselves, however, can only function when activated to become effector cells. The major surface marker of helper T cells is CD4.
- Memory T cells consist of both CD4 and CD8 T cells that can rapidly acquire effector functions to kill infected cells and/or secrete inflammatory cytokines that inhibit replication of the pathogen. Together with memory B cells, lymphocytes that store specific antigen messages after antigen stimulation have lifespans of up to several decades. When they receive the same antigenic stimuli as they once again, they can proliferate as functional T cells against antigen or plasma cells that produce antibodies.
- Regulatory / suppressor T cells often play an important role in maintaining their own tolerance and avoid excessive damage to the immune response to the body. There are many classes of regulatory / suppressor T cells, including CD25 and CD4 T cells. They can inhibit T cells and B cells to regulate and control the immune response and maintain immune self-stability.
Overview of T Cell Differentiation
In the thymus, developing T cell, known as thymocytes, proliferate and differentiate along developmental pathways that generate functionally distinct subpopulations of mature T cells. Aside from being the main source of all T cells, it is where T cells diversity and then are shaped into an effective primary T cell repertoire by an extraordinary pair of selection processes.
Cell differentiation is essential to create multiple subsets. Differentiation of na?ve T cells into effector cells is required for optimal protection against different classes of the microbial pathogen and for the development of immune memory. Differentiating cells undergo programmed alterations in their patterns of gene expression, which are regulated by structural changes in chromatin.
Differentiation is also directed by instructive and licensing signals from the environment, especially from antigen-presenting cells (APC). These cells gauge the class of the ingested microbe and generate signals that direct na?ve T cells to differentiate into the subset that mobilizes the appropriate immune defense mechanisms. It is widely believed that cytokines are the major drivers of differentiation. However, a purely cytokine-driven model is difficult to reconcile with evidence that antigen presentation and delivery of differentiation signals occur by one and the same APC. Therefore, a critical role may exist for short-range acting factors, such as cell surface molecules.
Differentiation of CD4 And CD8 T Cells
The past decade has seen the discovery of an ever-growing number of CD4 T helper cell subsets, with unique transcriptional programs governed by lineage-defining transcription factors. CD4 T helper cell subsets, known as T helper 1 (Th1), Th2, Th9, Th17, and Th22, each produce specific cocktails of cytokines to coordinate immunity to distinct types of microorganism. Follicular T helper cells (Tfh) specialize at helping B cells, while induced regulatory T cells (iTregs) suppress detrimental immune responses. Finally, a differentiation step is required to make T cells that contribute to immediate rejection of microbial infection, as well as others that develop into memory cells.
T helper type-1 (Th1) cells characteristically transcribe the T-bet transcription factor and produce interferon gamma (IFNg), interleukin-2 (IL-2), and lymphotoxin genes, whereas Th2 cells express the IL-4, IL-5, IL-6, IL-10, and IL-13 genes. Both Th1 and Th2 cells appear to derive from a common naive precursor cell whose differentiation pathway is determined by cytokine and costimulatory signals during primary antigenic stimulation. Specifically, Th1 differentiation is driven by IL-12 and requires the IL-12-responsive transcription factor STAT4, while Th2 differentiation is elicited by IL-4 and requires the IL-4- responsive transcription factor STAT6. In vivo, progressive polarization of the cytokine response occurs in response to chronic antigenic stimulation as a result of the self-amplification and negative cross regulation inherent in T cell differentiation. Th1 cells direct immunity against intracellular bacteria and viruses and have been implicated in a host of autoimmune conditions. However, Th2 cells do develop in helminth-infected mice even if IL4 receptor signaling has genetically been disabled, demonstrating the existence of other pathways that induce this differentiation program in vivo. Th2 cell responses were also reduced by GSI in a model or asthma.
CD8 T cell proliferation is dependent on repeated encounters with antigen. Each cell that is stimulated by antigen divides and progressively differentiates into effector cytotoxic T lymphocytes (CTLs) then memory CD8 T cells with each successive cell division. The initial antigenic stimulus triggers this developmental programme, such that the CD8 T cells become committed to proliferation and differentiation. Further antigenic stimulation of the daughter cells might increase the number of times the activated CD8 T cells divide, but it is not necessary to complete this developmental programme.
The programmed development of CD8 T cells has several advantages. First, it alleviates the need for prolonged confinement of CTLs to the lymphoid organs, which allows their migration to peripheral sites of infection and/or inflammation to remove infected cells. Second, it might also considerably affect the number of memory CD8 T cells that are generated, because the size of the memory T cell pool is directly correlated to that of the effector-cell population1–3. In several models of acute viral and bacterial infection, the number of effector CD8 T cells peaks 2–3 days after the infectious pathogen is cleared. If each CD8 T cell division was regulated strictly by antigen contact, the number of effector CTLs would peak earlier and reach a lower maximum, and consequently, fewer memory CD8 T cells would be generated.
The development of effector T cell responses is tightly coupled to clonal expansion. Studies have shown that the link between the commitment to clonal expansion and effector-cell differentiation is remarkably tight the same duration of antigenic stimulation (2–24 hours) that drove na?ve CD8 T cells to proliferate was sufficient for them to commit to differentiate into effector cells, tumour-necrosis factor (TNF) and IL-2, and kill infected cells.
Diseases and Treatment of T Cell Differentiation
Helper T (Th) lymphocytes undergo two spatially and temporally distinct phases of differentiation. Following the first developmental phase, which occurs in the thymus, a second phase triggered by the initial encounter with antigen in the periphery leads to the development of effector T helper cell subsets displaying mutually exclusive patterns of cytokine gene expression. Clinically, Th1 patterns of cytokine production are associated with inflammation and autoimmune disease while Th2 patterns are characteristic of allergic responses and asthma. Such as systemic lupus erythematosus (SLE), it is an autoimmune disease with unknown etiology affecting more than one million individuals each year. SLE is characterized by B and T cell hyperactivity and by defects in the clearance of apoptotic cells and immune complexes. Understanding the complex process involved and the interaction between various cytokines, chemokines, signaling molecules, and pattern-recognition receptors (PRRs) in the immune pathways will provide valuable information on the development of novel therapeutic targets for treating SLE disease.
Antibody and T cell responses to a single dose of the AZD1222/Covishield vaccine in previously SARS-CoV-2 infected and naïve health care workers in Sri Lanka
Background In order to determine the immunogenicity of a single dose of the AZD1222/Covishield vaccine in a real-world situation, we assessed the immunogenicity, in a large cohort of health care workers in Sri Lanka.
Methods SARS-CoV-2 antibodies was carried out in 607 naïve and 26 previously infected health care workers (HCWs) 28 to 32 days following a single dose of the vaccine. Haemagglutination test (HAT) for antibodies to the receptor binding domain (RBD) of the wild type virus, B.1.1.7, B.1.351 and the surrogate neutralization assay (sVNT) was carried out in 69 naïve and 26 previously infected individuals. Spike protein (pools S1 and S2) specific T cell responses were measured by ex vivo ELISpot IFNγ assays in 76 individuals.
Results 92.9% of previously naive HCWs seroconverted to a single dose of the vaccine, irrespective of age and gender and ACE2 blocking antibodies were detected in 67/69 (97.1%) previously naïve vaccine recipients. Although high levels of antibodies were found to the RBD of the wild type virus, the titres for B.1.1.7 and B.1.351 were lower in previously naïve HCWs. Ex vivo T cell responses were observed to S1 in 63.9% HCWs and S2 in 31.9%. The ACE2 blocking titres measured by the sVNT significantly increased (p<0.0001) from a median of 54.1 to 97.9 % of inhibition, in previously infected HCWs and antibodies to the RBD for the variants B.1.1.7 and B.1.351 also significantly increased.
Discussion a single dose of the AZD1222/Covishield vaccine was shown to be highly immunogenic in previously naïve individuals inducing antibody levels greater than following natural infection. In infected individuals, a single dose induced very high levels of ACE2 blocking antibodies and antibodies to RBDs of SARS-CoV-2 variants of concern.
Funding We are grateful to the World Health Organization, UK Medical Research Council and the Foreign and Commonwealth Office.
Competing Interest Statement
GNM is in the National Medicinal Regulatory Authority on the expert advisory panel in COVID-19 vaccines. SS in the Chief Epidemiologist in Sri Lanka and is involved in deciding vaccine priority lists.
We are grateful to the World Health Organization, UK Medical Research Council and the Foreign and Commonwealth Office for support. T.K.T. is funded by the Townsend-Jeantet Charitable Trust (charity number 1011770) and the EPA Cephalosporin Early Career Researcher Fund. A.T. are funded by the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Science (CIFMS), China (grant no. 2018-I2M-2-002).
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Ethics approval was obtained from the Ethics Review Committee of University of Sri Jayewardenepura.
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Trispecific antibodies offer a third way forward for anticancer immunotherapy
Alfred L. Garfall is in the Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
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Carl H. June is in the Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
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Antibodies with specificity for one target — called monoclonal antibodies — were the first cancer immunotherapy to achieve widespread clinical use. The therapeutic potency of antibodies can be amplified by engineering them to recognize two distinct molecular targets (termed antigens). These bispecific antibodies can simultaneously bind to cancer cells and immune cells called T cells, and this dual binding directs the T cell to unleash its cell-killing power towards the cancer cell. Writing in Nature Cancer, Wu et al. 1 now report the development of a trispecific antibody, one that has three targets: a cancer cell, a receptor that activates T cells, and a T-cell protein that promotes long-lasting T-cell activity against the cancer cell (Fig. 1).
Figure 1 | An antibody that helps immune cells to target cancer cells. Wu et al. 1 report the development of a human antibody that is engineered to bring an immune cell called a T cell into close proximity with a type of cancer cell called a myeloma cell and to boost the T cell’s anticancer response. This trispecific antibody binds three targets: the protein CD38 on a myeloma cell, and the protein CD28 and the protein complex CD3 on a T cell (the antibody’s target-binding domains are shown in red, blue and yellow, respectively). CD3 is part of the T-cell receptor (TCR), which recognizes abnormal cells by binding molecules called antigens. The binding of CD3 by the antibody drives T-cell activation (without requiring antigen recognition by the TCR), which leads to the killing of the myeloma cell and the production and release of toxic cytokine molecules. Binding of CD28 by the antibody drives expression of the protein Bcl-xL. Bcl-xL blocks T-cell death, which might otherwise occur if there was prolonged TCR activation in the absence of CD28 stimulation by the antibody.
The mammalian immune system generates an immense diversity of antibodies, and antibodies can also be engineered to recognize therapeutic targets. Antibodies usually recognize a single antigen, which might be part of a disease-causing agent or an abnormal version of a protein or sugar. Such monospecific antibodies against targets on cancer cells can recruit immune cells, including neutrophils, natural killer cells and macrophages, to kill or ingest the cancer cells.
Antibodies can also be engineered to block or stimulate the function of the proteins to which they bind. For example, there are regulatory receptors that inhibit T-cell function, and antibodies that have been engineered to block these receptors provide a clinical strategy known as checkpoint blockade, which boosts T-cell function. These inhibitory receptors govern T-cell exhaustion, a non-functional T-cell state that protects against autoimmunity and that can occur in the tumour microenvironment as cancers evade antitumour responses mediated by T cells. Checkpoint-blockade treatment can awaken exhausted antitumour T cells to great clinical benefit, but it also risks causing autoimmune toxicity. The antibody developed by Wu and colleagues takes a similar approach to promote T-cell activity against cancer cells. However, their method stimulates the function of receptors that positively boost T-cell function, rather than blocking the function of inhibitory receptors.
Read the paper: Trispecific antibodies enhance the therapeutic efficacy of tumor-directed T cells through T cell receptor co-stimulation
The human antibody developed by Wu et al. builds on bispecific-antibody technology that reconfigures the antigen-recognition domains of two different antibodies into one bispecific molecule. Bispecific antibodies usually target one antigen on the cancer cell’s surface and one on a protein complex on T cells called CD3. CD3 is part of the T-cell receptor (TCR) complex. The TCR also includes antigen-recognition domains and delivers an activating signal to the T cell when an antigen binds. Engagement of CD3 by the antibody also generates an activating signal. Such a bispecific antibody therefore activates T cells, brings them into close proximity to cancer cells — irrespective of the T cell’s natural antigen specificity — and redirects their killing capabilities towards the cancer cells.
This concept has proved to be clinically effective for the bispecific antibody blinatumomab, which targets CD3 and the protein CD19 on cancer cells. Blinatumomab treatment doubles the remission rate and survival among people with an advanced stage of a cancer called B-cell acute lymphoblastic leukaemia (B-ALL) 2 , and it is being tested as part of the initial therapy for B-ALL, with promising early results 3 .
Wu and colleagues devised a clever strategy to simultaneously boost T-cell activation and enhance the targeting of cancer cells in relation to multiple myeloma, which is a cancer of plasma cells in the blood. The authors developed a trispecific antibody that was engineered to have three antigen-binding sites, rather than two. This trispecific antibody targets CD3 plus the proteins CD38 (on cancer cells) and CD28 (on T cells). The CD38-targeting antibody daratumumab is clinically effective in treating this disease 4 , and CD38 is also a potential target in other cancers, such as acute lymphoid leukaemia and acute myeloid leukaemia.
CD28 belongs to a class of protein called co-stimulatory receptors, which positively regulate T-cell activation. When a T cell recognizes its target antigen through the TCR, the extra engagement of a co-stimulatory receptor such as CD28 is needed to achieve the sustained T-cell proliferation required for an effective immune response. In the absence of co-stimulation, activation through the TCR can lead to a state of T-cell non-responsiveness called anergy, or to the related state of exhaustion. Prolonged activation of the TCR without co-stimulation can lead the T cell to undergo a form of programmed cell death called apoptosis.
The addition of a co-stimulatory signal such as CD28 is notable because this signal has also been incorporated into another type of immunotherapy called chimaeric-antigen receptor T cell (CAR‑T) therapy 5 , in which a receptor is engineered to both recognize a cancer-cell antigen and include T-cell activation domains such as CD3 and CD28. The main reason for including a CD28-binding domain in the trispecific antibody is T-cell co-stimulation. However, CD28 is also frequently expressed by multiple myeloma cells, so this might increase the antibody’s affinity for the myeloma cells, and thus enable it to bind to cells in which CD38 is low, absent or masked by previous daratumumab therapy.
Teamwork by different T-cell types boosts tumour destruction by immunotherapy
To confirm that the CD28-binding domain augmented the trispecific antibody’s activity, the authors made versions of the antibody in which different combinations of the three binding domains were mutated. They tested these versions in ‘humanized’ model mice, which had human T cells and human myeloma cells. A functional CD28-targeting domain boosted T-cell activation above that observed using antibodies lacking this domain. This augmented T-cell activation drove T-cell proliferation and the expression of the anti-apoptotic protein Bcl-xL in T cells, supporting the authors’ hypothesis that having a co-stimulatory signal would prevent T-cell apoptosis. The presence of the CD28-targeting domain on the antibody boosted the ability of T cells to kill different myeloma cell lines in vitro and in the humanized mouse model, even at the lowest antibody dose tested.
The main limitation of this study is that the risk of a side effect called cytokine release syndrome (CRS), which can occur if the immune system is highly stimulated, is unknown. In CRS, the simultaneous activation of many T cells causes excessive release of signalling molecules called cytokines from cells of the immune system, which drives inflammation. CRS can occur with bispecific antibodies and with CAR-T. It typically manifests as fever, but can progress to fatal multi-organ failure in severe cases 6 .
The authors report cytokine-related toxicities with their trispecific antibody when administered to monkeys by intravenous injection, but toxicity was less if it was delivered under the skin (subcutaneously) instead, leading to a more gradual exposure to the antibody. It is reassuring that the inclusion of the CD28-targeting domain did not lead to overwhelming CRS in these tests. However, a key caveat is that the amount of CD38 in monkeys is much less than in people with multiple myeloma, and the higher amount of CD38, and thus of antibody-mediated T-cell activation, would probably increase the risk of CRS in humans. But in terms of possible negative effects of the antibody on healthy non-cancerous cells, it is reassuring that only transient decreases in the number of normal white blood cells that express CD38, such as lymphocytes and myeloid cells, were observed in monkeys treated with the antibody. Another limitation of the study is that the authors did not assess whether this trispecific antibody format might trigger an immune response against the antibody and cause its rapid destruction.
Targeting cancer using a trispecific antibody is an important conceptual advance, building on previous work by this group 7 on a trispecific antibody that targets HIV. For multiple myeloma, fresh therapeutic approaches are needed, because even the most potent emerging therapies, including a CAR-T that targets an antigen called BCMA, are only temporarily effective for most people 8 – 10 . A trispecific antibody is a flexible platform that might offer a way to deliver precise combinations of immunomodulatory signals (for example, a co-stimulatory signal and a checkpoint blocker) specifically in the tumour microenvironment, which might be safer and more effective than the systemic administration of combinations of individual, single-specificity immunomodulatory antibodies. Such efforts to make immunotherapy more precise and potent than it is at present might be necessary to broaden the reach of immunotherapy to include the many types of cancer that have so far proved difficult to target.
The immune system needs to be able to sense molecules that might be harmful to the organism. Such harmful molecules are known as antigens. Two classes of receptor proteins that mediate antigen recognition are antibodies and T-Cell receptors (TCRs). Antibodies are able to bind a diverse range of antigen shapes whilst TCRs are specialised to recognise a cell-surface protein, the pMHC. Antibodies that bind the pMHC are rarely created naturally. However, such TCR-like antibodies are of therapeutic importance. The binding regions of the TCR and the antibody have very similar three dimensional structures. Both consist of two independent units, domains, which associate and form the antigen binding site between them. This work examines how the two domains orientate with respect to one another in TCRs and antibodies. Our results show that the conformations that exist in TCRs and antibodies are distinct. Consequently it is difficult for an antibody to bind to a pMHC in the same way a TCR would. However, a similar conformation can be achieved in antibodies as in TCRs by the presence of certain amino-acids in the domain interface. This knowledge should aid the development of therapeutic TCR-like antibodies.
Citation: Dunbar J, Knapp B, Fuchs A, Shi J, Deane CM (2014) Examining Variable Domain Orientations in Antigen Receptors Gives Insight into TCR-Like Antibody Design. PLoS Comput Biol 10(9): e1003852. https://doi.org/10.1371/journal.pcbi.1003852
Editor: Yanay Ofran, Bar Ilan University, Israel
Received: April 18, 2014 Accepted: August 7, 2014 Published: September 18, 2014
Copyright: © 2014 Dunbar et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. Relevant data are within the paper and its Supporting Information files. Variable domain orientation angles may be found at opig.stats.ox.ac.uk/webapps/abangle.
Funding: JD is supported by the Engineering and Physical Sciences Research Council, UCB Pharma and F. Hoffmann-La Roche Ltd. JS is an employee of UCB Pharma and AF is an employee of F. Hoffmann-La Roche and had contributed to study design, analysis and preparation of the manuscript. Otherwise the funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: JS is an employee of UCB Pharma, AF is an employee of F. Hoffmann-La Roche, JD is partially funded by UCB Pharma and F. Hoffmann-La Roche. This does not alter our adherence to the PLOS policies on sharing data and materials. All other authors have declared that no competing interests exist.
Acute SARS-CoV-2 infection elicits distinct antibody, T-cell responses
February 1, 2021 -- An analysis of antibody and T-cell responses during the entire timeline of SARS-CoV-2 infection reveals the different ways the immune system responds to the virus in the early phases of COVID-19 disease. The results, published in Cell Reports on January 21, suggest that T-cell responses may be important for controlling infection while antibodies provide longer protection.
SARS-CoV-2 infection elicits both virus-specific humoral (antibody responses produced by B cells) and cellular (antigen-triggered T-cell responses) immunity. However, their independent roles on viral control and disease pathogenesis require further clarification.
Reduced disease severity has been associated with virus-specific T-cell responses and/or SARS-CoV-2 antibodies. However, most of this data come from studies analyzing patients during the convalescent period and not during active infection.
The researchers at Duke-National University of Singapore (NUS) Medical School followed 12 patients with SARS-CoV-2 infection from symptom onset to convalescence or death. They quantified SARS-CoV-2 viral load in the upper respiratory tract and SARS-CoV-2-specific antibodies and T cells at multiple time points.
"We found that patients who control SARS-Cov-2 infection with only mild symptoms are characterized by an early induction of IFN-γ secreting SARS-CoV-2 specific T cells. The amount of humoral response, however, does not predict the level of COVID-19 disease severity," said co-author Anthony Tanoto Tan, PhD, senior research fellow at the Duke-NUS Emerging Infectious Diseases (EID) program, in a statement.
T-cell responses do not correlate to more severe COVID-19 disease
Using an interferon (IFN)-γ enzyme-linked immunospot (ELISPOT) assay, the researchers assessed T-cell responses in epitopes across the spike protein, including the whole nucleoprotein (NP), membrane (M), the open reading frames (ORF)7ab, ORF8, ORF3a, the nonstructural protein (NSP)7, and the NSP13 of ORF1ab.
They observed that the overall magnitude of SARS-CoV-2 specific T cells was not proportional to the severity of disease. There were higher frequencies of IFN-γ-secreting cells in both early stages (day one-15) and late stages (day 15-30) were present in mild COVID-19 patients but not in moderate/severe patients.
They also found a statistically significant direct correlation between early appearance of SARS-CoV-2 peptide-reactive cells (specific for NP, ORF7/8, ORF3a, M, and the spike protein) and a shorter duration of infection.
"Our data supports the idea that SARS-CoV-2 specific T cells play an important role in the rapid control of viral infection and eventual clearance of the disease," added co-author Martin Linster, PhD, senior research fellow with the Duke-NUS EID program.
"It is time that T cell monitoring should be considered in providing a comprehensive understanding of the immune response against SARS-CoV-2. This would also mean that a vaccine will likely be more effective if a holistic induction of both antibodies and T cells occurs," said senior author, Antonio Bertoletti, PhD, professor at the Duke-NUS EID program.
Antibody responses do correlate to more severe COVID-19 disease
In the study, the most severe cases of COVID-19 showed the most rapid and robust ability to neutralize the virus and therefore the highest overall quantities of SARS-CoV-2-specific antibodies. The researchers characterized virus neutralization using a surrogate virus neutralization test that quantified the ability of serum antibodies to inhibit binding of the spike receptor binding domain to the angiotensin-converting enzyme 2 (ACE2) receptor in vitro.
The peak neutralizing activity in patients was achieved within nine-15 days after symptom onset. Patients with moderate/severe symptoms exhibited stronger virus-specific antibody responses than those with mild disease. Most peptide-responsive T cells were CD4 cells, but CD8 T cells specific to NP peptide pools were also detected. Because the frequency of SARS-CoV-2-specific T cells rapidly waned after SARS-CoV-2 clearance, the authors noted that the time of T-cell analysis can significantly influence the magnitude of the T-cell response detected.
ORF7/8-specific T cells were preferentially detected during the acute phase of infection, which corresponded to an increase in ORF8-specific antibodies during the early phases of SARS-CoV-2 infection. This triggered a robust IFN-γ response preferentially in the early phases of infection but only in patients with mild disease. Furthermore, these patients with mild symptoms cleared the virus early in the disease progression.
"This important study furthers our understanding of the immune response against SARS-CoV-2. It has far-reaching implications including on COVID-19 vaccine design and the subsequent monitoring of vaccine response," said Patrick Casey, PhD, senior vice dean for research at Duke-NUS.
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active immunity: immunity developed from an individual’s own immune system
central tolerance: B cell tolerance induced in immature B cells of the bone marrow
class switching: ability of B cells to change the class of antibody they produce without altering the specificity for antigen
clonal anergy: process whereby B cells that react to soluble antigens in bone marrow are made nonfunctional
clonal deletion: removal of self-reactive B cells by inducing apoptosis
Fc region: in an antibody molecule, the site where the two termini of the heavy chains come together many cells have receptors for this portion of the antibody, adding functionality to these molecules
heavy chain: larger protein chain of an antibody
IgA: antibody whose dimer is secreted by exocrine glands, is especially effective against digestive and respiratory pathogens, and can pass immunity to an infant through breastfeeding
IgD: class of antibody whose only known function is as a receptor on naive B cells important in B cell activation
IgE: antibody that binds to mast cells and causes antigen-specific degranulation during an allergic response
IgG: main blood antibody of late primary and early secondary responses passed from mother to unborn child via placenta
IgM: antibody whose monomer is a surface receptor of naive B cells the pentamer is the first antibody made blood plasma during primary responses
immunoglobulin: protein antibody occurs as one of five main classes
light chain: small protein chain of an antibody
passive immunity: transfer of immunity to a pathogen to an individual that lacks immunity to this pathogen usually by the injection of antibodies
peripheral tolerance: mature B cell made tolerant by lack of T cell help
T cell-dependent antigen: antigen that binds to B cells, which requires signals from T cells to make antibody
T cell-independent antigen: binds to B cells, which do not require signals from T cells to make antibody