SARS-CoV-2 spike T cell responses induced upon vaccination or infection remain robust against Omicron

The SARS-CoV-2 Omicron variant has multiple Spike (S) protein mutations that contribute to escape from the neutralizing antibody responses, and reducing vaccine protection from infection. The extent to which other components of the adaptive response such as T cells may still target Omicron and contribute to protection from severe outcomes is unknown. We assessed the ability of T cells to react with Omicron spike in participants who were vaccinated with Ad26.CoV2.S or BNT162b2, and in unvaccinated convalescent COVID-19 patients (n = 70). We found that 70-80% of the CD4 and CD8 T cell response to spike was maintained across study groups. Moreover, the magnitude of Omicron cross-reactive T cells was similar to that of the Beta and Delta variants, despite Omicron harbouring considerably more mutations. Additionally, in Omicron-infected hospitalized patients (n = 19), there were comparable T cell responses to ancestral spike, nucleocapsid and membrane proteins to those found in patients hospitalized in previous waves dominated by the ancestral, Beta or Delta variants (n = 49). These results demonstrate that despite Omicron's extensive mutations and reduced susceptibility to neutralizing antibodies, the majority of T cell response, induced by vaccination or natural infection, cross-recognises the variant. Well-preserved T cell immunity to Omicron is likely to contribute to protection from severe COVID-19, supporting early clinical observations from South Africa.

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A Novel Splenocyte Approach for Characterizing T Cell Responses to Adeno-Associated Virus in the Normal Population: Implications on Gene Transfer.

Blood ◽

10.1182/blood.v108.11.3258.3258 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3258-3258

Author(s):

Daniel J. Hui ◽

Federico Mingozzi ◽

Marcela V. Maus ◽

Michael A. Tigges ◽

Glenn F. Pierce ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Gene Transfer ◽

Cell Response ◽

Neutralizing Antibodies ◽

T Cell Responses ◽

T Cell Response ◽

Normal Donor ◽

Memory T Cell ◽

Cell Responses

Abstract Gene transfer using adeno-associated viral (AAV) vectors offers a promising strategy for the treatment of hemophilia B. However, in the first clinical trial using AAV-2 to deliver Factor IX (F.IX) into the liver via the hepatic artery, transgene expression was short-lived, followed by a gradual decline in F.IX levels and a transient rise in liver enzymes (Manno et al., 2006). We hypothesize this outcome was caused by a memory T cell response to a previous infection with wild-type AAV-2, which led to T cell-mediated destruction of transduced hepatocytes upon recognition of capsid sequences during gene transfer. No immune response to F.IX was detected. In order to further investigate the role that previous exposure to AAV-2 may have on limiting the duration of gene transfer, a normal donor population consisting of 46 adult subjects was tested for AAV-2 neutralizing antibodies and frequencies of circulating capsid-specific T cells by ELISpot assay. More than half (25/46) of the subjects had readily detectable titers of neutralizing antibodies to AAV-2 in serum. However, the prevalence of AAV-2 capsid-specific T cells detected by IFN-γ ELISpot in PBMCs was very low and positive responses could be confirmed in only 2/46 subjects. Attempts to expand the relevant T cell population in vitro, in which PBMCs were stimulated with the relevant AAV-2 peptide epitope, did not increase the frequency of detectable T cell responses. These results suggest that current methods may not be sensitive enough to fully appreciate the prevalence of AAV-2-specific CD8+ memory T cells in humans because they circulate at frequencies that are commonly too low for detection, as indicated by the discrepancy between the presence of AAV neutralizing antibodies and the observed T cell response. Moreover, it is possible that AAV-specific CD8+ T cells fail to circulate but rather reside in lymphatic compartments. To address this problem, we developed an alternative approach using human splenocytes. Splenocytes offer two critical advantages: they permit sampling of a primary lymphoid organ, and they can be obtained in much higher overall cell numbers than PBMCs. Using splenocytes obtained from both normal donor adults and children undergoing splenectomy, T cell responses via ELISpot assay have been detected in 7 out of 27 subjects, reflecting a higher frequency (26%) of observed T cell responses than that seen using PBMCs. In addition, intracellular cytokine staining analysis for IFN-γ confirmed the presence of AAV capsid-specific CD8+ T cells in the samples tested. Interestingly, in the current study T cell responses were seen in donors as young as 5 years of age, while more robust responses were seen in adult patients >37 years of age. These results have important implications for gene transfer with AAV; specifically, that children as young as 5 years old have detectable T cell responses to AAV capsid and could thus mount a memory T cell response on vector infusion. We conclude that memory T-cell-mediated immune responses to viral capsids in the normal population is more common than PBMC-based assays suggest, and given the observed cross-reactivity among AAV serotypes (see abstract by Mingozzi et al.), these results may affect not only AAV-2 clinical trials, but other AAV clinical trials as well.

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126. Magnitude and Dynamics of the T-Cell Response to SARS-CoV-2 Infection and Vaccination

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab466.126 ◽

2021 ◽

Vol 8 (Supplement_1) ◽

pp. S77-S77

Author(s):

Thomas M Snyder ◽

Rachel M Gittelman ◽

Mark Klinger ◽

Damon H May ◽

Edward J Osborne ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

T Cell ◽

Cell Response ◽

Natural Infection ◽

T Cell Responses ◽

T Cell Response ◽

Cell Responses ◽

Tcr Repertoire ◽

Repertoire Sequencing

Abstract Background T cells are central to the early identification and clearance of viral infections and support antibody generation by B cells, making them desirable for assessing the immune response to SARS-CoV-2 infection and vaccines. We combined 2 high-throughput immune profiling methods to create a quantitative picture of the SARS-CoV-2 T-cell response that is highly sensitive, durable, diagnostic, and discriminatory between natural infection and vaccination. Methods We deeply characterized 116 convalescent COVID-19 subjects by experimentally mapping CD8 and CD4 T-cell responses via antigen stimulation to 545 Human Leukocyte Antigen (HLA) class I and 284 class II viral peptides. We also performed T-cell receptor (TCR) repertoire sequencing on 1815 samples from 1521 PCR-confirmed SARS-CoV-2 cases and 3500 controls to identify shared public TCRs from SARS-CoV-2-associated CD8 and CD4 T cells. Combining these approaches with additional samples from vaccinated individuals, we characterized the response to natural infection as well as vaccination by separating responses to spike protein from other viral targets. Results We find that T-cell responses are often driven by a few immunodominant, HLA-restricted epitopes. As expected, the SARS-CoV-2 T-cell response peaks about 1-2 weeks after infection and is detectable at least several months after recovery. Applying these data, we trained a classifier to diagnose past SARS-CoV-2 infection based solely on TCR sequencing from blood samples and observed, at 99.8% specificity, high sensitivity soon after diagnosis (Day 3–7 = 85.1%; Day 8–14 = 94.8%) that persists after recovery (Day 29+/convalescent = 95.4%). Finally, by evaluating TCRs binding epitopes targeting all non-spike SARS-CoV-2 proteins, we were able to separate natural infection from vaccination with > 99% specificity. Conclusion TCR repertoire sequencing from whole blood reliably measures the adaptive immune response to SARS-CoV-2 soon after viral antigenic exposure (before antibodies are typically detectable) as well as at later time points, and distinguishes post-infection vs. vaccine immune responses with high specificity. This approach to characterizing the cellular immune response has applications in clinical diagnostics as well as vaccine development and monitoring. Disclosures Thomas M. Snyder, PhD, Adaptive Biotechnologies (Employee, Shareholder) Rachel M. Gittelman, PhD, Adaptive Biotechnologies (Employee, Shareholder) Mark Klinger, PhD, Adaptive Biotechnologies (Employee, Shareholder) Damon H. May, PhD, Adaptive Biotechnologies (Employee, Shareholder) Edward J. Osborne, PhD, Adaptive Biotechnologies (Employee, Shareholder) Ruth Taniguchi, PhD, Adaptive Biotechnologies (Employee, Shareholder) H. Jabran Zahid, PhD, Microsoft Research (Employee, Shareholder) Rebecca Elyanow, PhD, Adaptive Biotechnologies (Employee, Shareholder) Sudeb C. Dalai, MD, PhD, Adaptive Biotechnologies (Employee, Shareholder) Ian M. Kaplan, PhD, Adaptive Biotechnologies (Employee, Shareholder) Jennifer N. Dines, MD, Adaptive Biotechnologies (Employee, Shareholder) Matthew T. Noakes, PhD, Adaptive Biotechnologies (Employee, Shareholder) Ravi Pandya, PhD, Microsoft Research (Employee, Shareholder) Lance Baldo, MD, Adaptive Biotechnologies (Employee, Shareholder, Leadership Interest) James R. Heath, PhD, Merck (Research Grant or Support, Funding (from BARDA) for the ISB INCOV project, but had no role in planning the research or in writing the paper.) Joaquin Martinez-Lopez, MD, PhD, Adaptive Biotechnologies (Consultant) Jonathan M. Carlson, PhD, Microsoft Research (Employee, Shareholder) Harlan S. Robins, PhD, Adaptive Biotechnologies (Board Member, Employee, Shareholder)

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Role of Thymic Output in Regulating CD8 T-Cell Homeostasis during Acute and Chronic Viral Infection

Journal of Virology ◽

10.1128/jvi.79.15.9419-9429.2005 ◽

2005 ◽

Vol 79 (15) ◽

pp. 9419-9429 ◽

Cited By ~ 29

Author(s):

Nicole E. Miller ◽

Jennifer R. Bonczyk ◽

Yumi Nakayama ◽

M. Suresh

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Cell Response ◽

Viral Infections ◽

T Cell Responses ◽

Cd8 T Cell ◽

T Cell Response ◽

Cell Responses ◽

Lcmv Infection

ABSTRACT Although it is well documented that CD8 T cells play a critical role in controlling chronic viral infections, the mechanisms underlying the regulation of CD8 T-cell responses are not well understood. Using the mouse model of an acute and chronic lymphocytic choriomeningitis virus (LCMV) infection, we have examined the relative importance of peripheral T cells and thymic emigrants in the elicitation and maintenance of CD8 T-cell responses. Virus-specific CD8 T-cell responses were compared between mice that were either sham thymectomized or thymectomized (Thx) at ∼6 weeks of age. In an acute LCMV infection, thymic deficiency did not affect either the primary expansion of CD8 T cells or the proliferative renewal and maintenance of virus-specific lymphoid and nonlymphoid memory CD8 T cells. Following a chronic LCMV infection, in Thx mice, although the initial expansion of CD8 T cells was normal, the contraction phase of the CD8 T-cell response was exaggerated, which led to a transient but striking CD8 T-cell deficit on day 30 postinfection. However, the virus-specific CD8 T-cell response in Thx mice rebounded quickly and was maintained at normal levels thereafter, which indicated that the peripheral T-cell repertoire is quite robust and capable of sustaining an effective CD8 T-cell response in the absence of thymic output during a chronic LCMV infection. Taken together, these findings should further our understanding of the regulation of CD8 T-cell homeostasis in acute and chronic viral infections and might have implications in the development of immunotherapy.

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DNA gag/Adenovirus Type 5 (Ad5) gag and Ad5 gag/Ad5 gag Vaccines Induce Distinct T-Cell Response Profiles

Journal of Virology ◽

10.1128/jvi.00620-08 ◽

2008 ◽

Vol 82 (16) ◽

pp. 8161-8171 ◽

Cited By ~ 40

Author(s):

Kara S. Cox ◽

James H. Clair ◽

Michael T. Prokop ◽

Kara J. Sykes ◽

Sheri A. Dubey ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Response ◽

T Cell Responses ◽

Adenovirus Type ◽

T Cell Response ◽

Cell Responses ◽

Response Profiles ◽

Adenovirus Type 5 ◽

Hiv 1

ABSTRACT Results from Merck's phase II adenovirus type 5 (Ad5) gag/pol/nef test-of-concept trial showed that the vaccine lacked efficacy against human immunodeficiency virus (HIV) infection in a high-risk population. Among the many questions to be explored following this outcome are whether (i) the Ad5 vaccine induced the quality of T-cell responses necessary for efficacy and (ii) the lack of efficacy in the Ad5 vaccine can be generalized to other vector approaches intended to induce HIV type 1 (HIV-1)-specific T-cell responses. Here we present a comprehensive evaluation of the T-cell response profiles from cohorts of clinical trial subjects who received the HIV CAM-1 gag insert delivered by either a regimen with DNA priming followed by Ad5 boosting (n = 50) or a homologous Ad5/Ad5 prime-boost regimen (n = 70). The samples were tested using a statistically qualified nine-color intracellular cytokine staining assay measuring interleukin-2 (IL-2), tumor necrosis factor alpha, macrophage inflammatory protein 1β, and gamma interferon production and expression of CD107a. Both vaccine regimens induced CD4+ and CD8+ HIV gag-specific T-cell responses which variably expressed several intracellular markers. Several trends were observed in which the frequencies of HIV-1-specific CD4+ T cells and IL-2 production from antigen-specific CD8+ T cells in the DNA/Ad5 cohort were more pronounced than in the Ad5/Ad5 cohort. Implications of these results for future vaccine development will be discussed.

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Activation-induced Markers Detect Vaccine-Specific CD4+ T Cell Responses Not Measured by Assays Conventionally Used in Clinical Trials

Vaccines ◽

10.3390/vaccines6030050 ◽

2018 ◽

Vol 6 (3) ◽

pp. 50 ◽

Cited By ~ 6

Author(s):

Georgina Bowyer ◽

Tommy Rampling ◽

Jonathan Powlson ◽

Richard Morter ◽

Daniel Wright ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Response ◽

Viral Vectors ◽

Comprehensive Evaluation ◽

T Cell Responses ◽

T Cell Response ◽

Cell Responses ◽

Vaccine Immunogenicity ◽

Sensitivity Specificity

Immunogenicity of T cell-inducing vaccines, such as viral vectors or DNA vaccines and Bacillus Calmette-Guérin (BCG), are frequently assessed by cytokine-based approaches. While these are sensitive methods that have shown correlates of protection in various vaccine studies, they only identify a small proportion of the vaccine-specific T cell response. Responses to vaccination are likely to be heterogeneous, particularly when comparing prime and boost or assessing vaccine performance across diverse populations. Activation-induced markers (AIM) can provide a broader view of the total antigen-specific T cell response to enable a more comprehensive evaluation of vaccine immunogenicity. We tested an AIM assay for the detection of vaccine-specific CD4+ and CD8+ T cell responses in healthy UK adults vaccinated with viral vectored Ebola vaccine candidates, ChAd3-EBO-Z and MVA-EBO-Z. We used the markers, CD25, CD134 (OX40), CD274 (PDL1), and CD107a, to sensitively identify vaccine-responsive T cells. We compared the use of OX40+CD25+ and OX40+PDL1+ in CD4+ T cells and OX40+CD25+ and CD25+CD107a+ in CD8+ T cells for their sensitivity, specificity, and associations with other measures of vaccine immunogenicity. We show that activation-induced markers can be used as an additional method of demonstrating vaccine immunogenicity, providing a broader picture of the global T cell response to vaccination.

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The Response to Repeated Vaccination with PR1 and WT1 Peptides Admixed in Montanide Adjuvant Is Transient and Fails to Induce Sustained Anti-Leukemia Responses in Patients with Myeloid Malignancies.

Blood ◽

10.1182/blood.v114.22.4096.4096 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4096-4096

Author(s):

Katayoun Rezvani ◽

Agnes S. M. Yong ◽

Stephan Mielke ◽

Behnam Jafarpour ◽

Bipin N. Savani ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Cell Response ◽

T Cell Responses ◽

Cd8 T Cell ◽

T Cell Response ◽

Gm Csf ◽

Cell Responses ◽

Ifn Γ

Abstract Abstract 4096 Poster Board III-1031 We previously demonstrated the immunogenicity of a combined vaccine approach employing two leukemia-associated antigenic peptides, PR1 and WT1 (Rezvani Blood 2008). Eight patients with myeloid malignancies received one subcutaneous 0.3 mg and 0.5 mg dose each of PR1 and WT1 vaccines in Montanide adjuvant, with 100 μg of granulocyte-macrophage colony-stimulating factor (GM-CSF). CD8+ T-cell responses against PR1 or WT1 were detected in all patients as early as 1 week post-vaccination. However, responses were only sustained for 3-4 weeks. The emergence of PR1 or WT1-specific CD8+ T-cells was associated with a significant but transient reduction in minimal residual disease (MRD) as assessed by WT1 expression, suggesting a vaccine-induced anti-leukemia response. Conversely, loss of response was associated with reappearance of WT1 transcripts. We hypothesized that maintenance of sustained or at least repetitive responses may require frequent boost injections. We therefore initiated a phase 2 study of repeated vaccination with PR1 and WT1 peptides in patients with myeloid malignancies. Five patients with acute myeloid leukemia (AML) and 2 patients with myelodysplastic syndrome (MDS) were recruited to receive 6 injections at 2 week intervals of PR1 and WT1 in Montanide adjuvant, with GM-CSF as previously described. Six of 7 patients completed 6 courses of vaccination and follow-up as per protocol, to monitor toxicity and immunological responses. Responses to PR1 or WT1 vaccine were detected in all patients after only 1 dose of vaccine. However, additional boosting did not further increase the frequency of PR1 or WT1-specific CD8+ T-cell response. In 4/6 patients the vaccine-induced T-cell response was lost after the fourth dose and in all patients after the sixth dose of vaccine. To determine the functional avidity of the vaccine-induced CD8+ T-cell response, the response of CD8+ T-cells to stimulation with 2 concentrations of PR1 and WT1 peptides (0.1 and 10 μM) was measured by IC-IFN-γ staining. Vaccination led to preferential expansion of low avidity PR1 and WT1 specific CD8+ T-cell responses. Three patients (patients 4, 6 and 7) returned 3 months following the 6th dose of PR1 and WT1 peptide injections to receive a booster vaccine. Prior to vaccination we could not detect the presence of PR1 and WT1 specific CD8+ T-cells by direct ex-vivo tetramer and IC-IFN-γ assay or with 1-week cultured IFN-γ ELISPOT assay, suggesting that vaccination with PR1 and WT1 peptides in Montanide adjuvant does not induce memory CD8+ T-cell responses. This observation is in keeping with recent work in a murine model where the injection of minimal MHC class I binding peptides derived from self-antigens mixed with IFA adjuvant resulted in a transient effector CD8+ T cell response with subsequent deletion of these T cells and failure to induce CD8+ T cell memory (Bijker J Immunol 2007). This observation can be partly explained by the slow release of vaccine peptides from the IFA depot without systemic danger signals, leading to presentation of antigen in non-inflammatory lymph nodes by non-professional antigen presenting cells (APCs). An alternative explanation for the transient vaccine-induced immune response may be the lack of CD4+ T cell help. In summary these data support the immunogenicity of PR1 and WT1 peptide vaccines. However new approaches will be needed to induce long-term memory responses against leukemia antigens. To avoid tolerance induction we plan to eliminate Montanide adjuvant and use GM-CSF alone. Supported by observations that the in vivo survival of CD8+ T-effector cells against viral antigens are improved by CD4+ helper cells, we are currently attempting to induce long-lasting CD8+ T-cell responses to antigen by inducing CD8+ and CD4+ T-cell responses against class I and II epitopes of WT1 and PR1. Disclosures: No relevant conflicts of interest to declare.

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EBV-positive lymphoma patients have a selective deficiency in EBV immunity

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.21032 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 21032-21032

Author(s):

K. N. Heller ◽

P. G. Steinherz ◽

C. S. Portlock ◽

C. Münz

Keyword(s):

Immune Response ◽

T Cells ◽

T Cell ◽

Immune Responses ◽

Healthy Volunteers ◽

Cell Response ◽

T Cell Responses ◽

T Cell Response ◽

Specific Immune Response ◽

Cell Responses

21032 Background: Epstein-Barr virus (EBV) asymptomatically establishes persistent infections in more than 90% of the adult population. However, due to effective immune control, only a minority of infected carriers develops spontaneous EBV-associated lymphomas. Since EBV nuclear antigen-1 (EBNA1) is the only protein expressed in all proliferating EBV infected cells we hypothesize that EBNA1 specific immune response is critical in preventing EBV-positive lymphomas. Methods: After informed consent, peripheral blood from healthy volunteers and lymphoma patients (prior to therapy- no evidence of cytopenia) were stimulated (ex vivo) with overlapping peptides covering the immunogenic EBNA1 (aa400–641) sequence. Frequency of EBNA1-specific T-cells were assessed by intracellular cytokine staining and flow cytometric proliferation assays. Cytokine pattern, surface marker phenotype and functional reactivity against EBV specific and control antigens were analyzed. Results: Patient and volunteer immune responses to control antigens and other viruses were assessed and statistically indistinguishable. EBNA1 specific CD4+ T cell responses were detected among 18 of 20 healthy carriers, and among 10 of 16 patients with EBV-negative lymphoma (relative to healthy volunteers p=0.145 via paired student T test). None of the patients with EBV-positive lymphomas (n=8) had a detectable EBNA1-specific CD4+ T-cell response (p<0.003 relative to healthy volunteers and patients with EBV-negative lymphomas). Conclusions: Healthy volunteers and patients with EBV-negative lymphoma have statistically similar EBNA1-specific CD4+ T cell responses. Although patients with EBV-positive lymphoma have intact immune responses to common viruses and antigens, they selectively lack an EBNA1-specific CD4+ T cell response. An intact EBNA1 specific immune response among patients with EBV-negaitve lymphoma implies that lymphoma is not a cause of a selective immune deficiency. On the contrary, these findings suggest that EBNA1-specific CD4+ T cells are critical in the prevention of EBV mediated lymphomas, and a defect in EBNA1 specific immunity may leave EBV carriers suseptible to EBV-positive lymphomas. EBNA1- specific CD4+ T cell function may be a new target for therapies of EBV-associated malignancies. No significant financial relationships to disclose.

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Defining kinetic properties of HIV-specific CD8+T-cell responses in acute infection

10.1101/158683 ◽

2017 ◽

Cited By ~ 2

Author(s):

Yiding Yang ◽

Vitaly V. Ganusov

Keyword(s):

T Cells ◽

Viral Load ◽

T Cell ◽

Cell Response ◽

Chronic Infection ◽

T Cell Responses ◽

T Cell Response ◽

Cell Responses ◽

Evenness Index ◽

Average Viral Load

AbstractMultiple lines of evidence indicate that CD8+T cells are important in the control of HIV-1 (HIV) replication. However, CD8+T cells induced by natural infection cannot eliminate the virus or reduce viral loads to acceptably low levels in most infected individuals. Understanding the basic quantitative features of CD8+T-cell responses induced during the course of HIV infection may therefore inform us about the limits that HIV vaccines, which aim to induce protective CD8+T-cell responses, must exceed. Using previously published experimental data from a cohort of HIV-infected individuals with sampling times from acute to chronic infection we defined the quantitative properties of CD8+T-cell responses to the whole HIV proteome. In contrast with a commonly held view, we found that the relative number of HIV-specific CD8+T-cell responses (response breadth) changed little over the course of infection (first 400 days post-infection), with moderate but statistically significant changes occurring only during the first 35 symptomatic days. This challenges the idea that a change in the T-cell response breadth over time is responsible for the slow speed of viral escape from CD8+T cells in the chronic infection. The breadth of HIV-specific CD8+T-cell responses was not correlated with the average viral load for our small cohort of patients. Metrics of relative immunodominance of HIV-specific CD8+T-cell responses such as Shannon entropy or the Evenness index were also not significantly correlated with the average viral load. Our mathematical-model-driven analysis suggested extremely slow expansion kinetics for the majority of HIV-specific CD8+T-cell responses and the presence of intra- and interclonal competition between multiple CD8+T-cell responses; such competition may limit the magnitude of CD8+T-cell responses, specific to different epitopes, and the overall number of T-cell responses induced by vaccination. Further understanding of mechanisms underlying interactions between the virus and virus-specific CD8+T-cell response will be instrumental in determining which T-cell-based vaccines will induce T-cell responses providing durable protection against HIV infection.AbbreviationsCTLcytotoxic T lymphocyteHIVhuman immunodeficiency virusSEShannon entropyEIEvenness indexPBMCperipheral blood mononuclear cellsSFCspot-forming cellsIFNinterferon

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Architecture of a minimal signalling pathway explains the T cell response to a 1,000,000-fold variation in antigen affinity and dose

10.1101/071878 ◽

2016 ◽

Cited By ~ 2

Author(s):

Melissa Lever ◽

Hong-Sheng Lim ◽

Philipp Kruger ◽

John Nguyen ◽

Nicola Trendel ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Response ◽

Mechanistic Model ◽

T Cell Responses ◽

T Cell Response ◽

Response Curves ◽

Cell Responses ◽

Cellular Signalling ◽

Different Doses

AbstractT cells must respond differently to antigens of varying affinity presented at different doses. Previous attempts to map pMHC affinity onto T cell responses have produced inconsistent patterns of responses preventing formulations of canonical models of T cell signalling. Here, a systematic analysis of T cell responses to 1,000,000-fold variations in both pMHC affinity and dose produced bell-shaped dose-response curves and different optimal pMHC affinities at different pMHC doses. Using sequential model rejection/identification algorithms, we identified a unique, minimal model of cellular signalling incorporating kinetic proofreading with limited signalling coupled to an incoherent feed forward loop (KPL-IFF), that reproduces these observations. We show that the KPL-IFF model correctly predicts the T cell response to antigen co-presentation. Our work offers a general approach for studying cellular signalling that does not require full details of biochemical pathways.Significance statementT cells initiate and regulate adaptive immune responses when their T cell antigen receptors recognise antigens. The T cell response is known to depend on the antigen affinity/dose but the precise relationship, and the mechanisms underlying it, are debated. To resolve the debate, we stimulated T cells with antigens spanning a 1,000,000-fold range in affinity/dose. We found that a different antigen (and hence different affinity) produced the largest T cell response at different doses. Using model identification algorithms, we report a simple mechanistic model that can predict the T cell response from the physiological low affinity regime into the high affinity regime applicable to therapeutic receptors.

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Long-term follow-up of SARS-CoV-2 convalescents reveals distinct magnitude of spike-specific immunity after viral re-exposure and vaccination

10.21203/rs.3.rs-677167/v1 ◽

2021 ◽

Author(s):

Percy Knolle ◽

Nina Körber ◽

Alina Priller ◽

Sarah Yazici ◽

Tanja Bauer ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Neutralizing Antibodies ◽

T Cell Responses ◽

T Cell Immunity ◽

Cell Responses ◽

Specific Immunity ◽

Cell Immunity

Abstract Infection with the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is controlled by the host´s immune response1-4, but longitudinal follow-up studies of virus-specific immunity to evaluate protection from re-infection are lacking. Here, we report the results from a prospective study that started during the first wave of the COVID-19 pandemic in spring 2020, where we identified 91 convalescents from mild SARS-CoV-2 infection among 4554 health care workers. We followed the dynamics and magnitude of spike-specific immunity in convalescents during the spontaneous course over ≥ 9 months, after SARS-CoV-2 re-exposure and after BNT162b2 mRNA vaccination. Virus-neutralizing antibodies and spike-specific T cell responses with predominance of IL-2-secreting polyfunctional CD4 T cells continuously declined over 9 months, but remained detectable at low levels. After a single vaccination, convalescents simultaneously mounted strong antibody and T cell responses against the SARS-CoV-2 spike proteins. In naïve individuals, a prime vaccination induced preferentially IL-2-secreting CD4 T cells that preceded production of spike-specific virus-neutralizing antibodies after boost vaccination. Response to vaccination, however, was not homogenous. Compared to four individuals among 455 naïve vaccinees (0.9%), we identified 5/82 (6.1%) convalescents with a delayed response to vaccination. These convalescents had originally developed dysfunctional spike-specific immune responses after SARS-CoV-2 infection, and required prime and boost vaccination to develop strong spike-specific immunity. Importantly, during the second wave of the COVID-19 pandemic in fall/winter of 2021 and prior to vaccination we detected a surge of virus-neutralizing antibodies consistent with re-exposure to SARS-CoV-2 in 6 out of 82 convalescents. The selective increase in virus-neutralizing antibodies occurred without systemic re-activation of spike-specific T cell immunity, whereas a single BNT162b2 mRNA vaccination sufficed to induce strong spike-specific antibody and systemic T cell responses in the same individuals. These results support the notion that BNT162b2 mRNA vaccination synchronizes spike-specific immunity in all convalescents of mild SARS-CoV-2 infection and may provide additional protection from re-infection by inducing more rigorous stimulation of spike-specific T cell immunity than re-exposure with SARS-CoV-2.

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