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1.
Front Immunol ; 13: 858057, 2022.
Article in English | MEDLINE | ID: covidwho-2005865

ABSTRACT

Sparked by the development of genome sequencing technology, the quantity and quality of data handled in immunological research have been changing dramatically. Various data and database platforms are now driving the rapid progress of machine learning for immunological data analysis. Of various topics in immunology, T cell receptor repertoire analysis is one of the most important targets of machine learning for assessing the state and abnormalities of immune systems. In this paper, we review recent repertoire analysis methods based on machine learning and deep learning and discuss their prospects.


Subject(s)
Immune System , Machine Learning , Receptors, Antigen, T-Cell/genetics
2.
J Exp Med ; 219(2)2022 02 07.
Article in English | MEDLINE | ID: covidwho-1984990

ABSTRACT

In rare instances, pediatric SARS-CoV-2 infection results in a novel immunodysregulation syndrome termed multisystem inflammatory syndrome in children (MIS-C). We compared MIS-C immunopathology with severe COVID-19 in adults. MIS-C does not result in pneumocyte damage but is associated with vascular endotheliitis and gastrointestinal epithelial injury. In MIS-C, the cytokine release syndrome is characterized by IFNγ and not type I interferon. Persistence of patrolling monocytes differentiates MIS-C from severe COVID-19, which is dominated by HLA-DRlo classical monocytes. IFNγ levels correlate with granzyme B production in CD16+ NK cells and TIM3 expression on CD38+/HLA-DR+ T cells. Single-cell TCR profiling reveals a skewed TCRß repertoire enriched for TRBV11-2 and a superantigenic signature in TIM3+/CD38+/HLA-DR+ T cells. Using NicheNet, we confirm IFNγ as a central cytokine in the communication between TIM3+/CD38+/HLA-DR+ T cells, CD16+ NK cells, and patrolling monocytes. Normalization of IFNγ, loss of TIM3, quiescence of CD16+ NK cells, and contraction of patrolling monocytes upon clinical resolution highlight their potential role in MIS-C immunopathogenesis.


Subject(s)
COVID-19/complications , Hepatitis A Virus Cellular Receptor 2/metabolism , Interferon-gamma/metabolism , Killer Cells, Natural/immunology , Monocytes/metabolism , Receptors, IgG/metabolism , Systemic Inflammatory Response Syndrome/immunology , T-Lymphocytes/immunology , Adolescent , Alveolar Epithelial Cells/pathology , B-Lymphocytes/immunology , Blood Vessels/pathology , COVID-19/immunology , COVID-19/pathology , Cell Proliferation , Child , Cohort Studies , Complement Activation , Cytokines/metabolism , Enterocytes/pathology , Female , Humans , Immunity, Humoral , Inflammation/pathology , Interferon Type I/metabolism , Interleukin-15/metabolism , Lymphocyte Activation/immunology , Male , Receptors, Antigen, T-Cell/metabolism , SARS-CoV-2/immunology , Superantigens/metabolism , Systemic Inflammatory Response Syndrome/pathology
3.
Proc Natl Acad Sci U S A ; 119(34): e2201541119, 2022 Aug 23.
Article in English | MEDLINE | ID: covidwho-1984598

ABSTRACT

Whereas pathogen-specific T and B cells are a primary focus of interest during infectious disease, we have used COVID-19 to ask whether their emergence comes at a cost of broader B cell and T cell repertoire disruption. We applied a genomic DNA-based approach to concurrently study the immunoglobulin-heavy (IGH) and T cell receptor (TCR) ß and δ chain loci of 95 individuals. Our approach detected anticipated repertoire focusing for the IGH repertoire, including expansions of clusters of related sequences temporally aligned with SARS-CoV-2-specific seroconversion, and enrichment of some shared SARS-CoV-2-associated sequences. No significant age-related or disease severity-related deficiencies were noted for the IGH repertoire. By contrast, whereas focusing occurred at the TCRß and TCRδ loci, including some TCRß sequence-sharing, disruptive repertoire narrowing was almost entirely limited to many patients aged older than 50 y. By temporarily reducing T cell diversity and by risking expansions of nonbeneficial T cells, these traits may constitute an age-related risk factor for COVID-19, including a vulnerability to new variants for which T cells may provide key protection.


Subject(s)
COVID-19 , Aged , B-Lymphocytes , COVID-19/genetics , Humans , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell, alpha-beta/genetics , SARS-CoV-2/genetics , T-Lymphocytes
4.
Immunity ; 55(7): 1299-1315.e4, 2022 07 12.
Article in English | MEDLINE | ID: covidwho-1977374

ABSTRACT

As the establishment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cell memory in children remains largely unexplored, we recruited convalescent COVID-19 children and adults to define their circulating memory SARS-CoV-2-specific CD4+ and CD8+ T cells prior to vaccination. We analyzed epitope-specific T cells directly ex vivo using seven HLA class I and class II tetramers presenting SARS-CoV-2 epitopes, together with Spike-specific B cells. Unvaccinated children who seroconverted had comparable Spike-specific but lower ORF1a- and N-specific memory T cell responses compared with adults. This agreed with our TCR sequencing data showing reduced clonal expansion in children. A strong stem cell memory phenotype and common T cell receptor motifs were detected within tetramer-specific T cells in seroconverted children. Conversely, children who did not seroconvert had tetramer-specific T cells of predominantly naive phenotypes and diverse TCRαß repertoires. Our study demonstrates the generation of SARS-CoV-2-specific T cell memory with common TCRαß motifs in unvaccinated seroconverted children after their first virus encounter.


Subject(s)
COVID-19 , SARS-CoV-2 , CD4-Positive T-Lymphocytes , CD8-Positive T-Lymphocytes , Epitopes, T-Lymphocyte , Humans , Immunologic Memory , Receptors, Antigen, T-Cell , Receptors, Antigen, T-Cell, alpha-beta/genetics , Spike Glycoprotein, Coronavirus
5.
Clin Lymphoma Myeloma Leuk ; 22(8): e730-e737, 2022 08.
Article in English | MEDLINE | ID: covidwho-1966439

ABSTRACT

INTRODUCTION: Chimeric antigen receptor T-cell therapy (CAR T) is a revolutionary adoptive immunotherapy approach in lymphoma; however, substantial resources are necessary for administration and care of these patients. Our institution has administered tisagenlecleucel primarily in an outpatient setting, and here we report our clinical outcomes. PATIENTS AND METHODS: We conducted a single institution, retrospective study investigating outcomes of adult lymphoma patients treated with commercial tisagenlecleucel between 10/2017 and 12/2020. We analyzed patient characteristics and outcomes of efficacy and safety including overall response rate, progression-free survival, overall survival and cytokine-release syndrome, neurotoxicity, and hospitalizations. RESULTS: Seventy-two patients with relapsed or refractory non-Hodgkin lymphoma (NHL) who received commercial tisagenlecleucel were identified; 68 (94.4%) patients received outpatient tisagenlecleucel. The overall response rate was 43% with a complete response observed in 25 patients (34.7%). At a median follow-up of 9.1 months, the median progression-free survival was 3.3 months. Grade 3-4 cytokine release syndrome was not observed in the study group and two patients had grade 3-4 neurotoxicity. Twenty-six patients (36.1%) were admitted within 30 days after infusion with a median length of stay of 5 days. Fourteen patients (19.4%) were admitted within 72 hours of infusion. No patient died of CAR T cell-related toxicity. CONCLUSION: Our experience affirms treatment with tisagenlecleucel in the outpatient setting is safe and feasible with close supervision and adequate institutional experience. After infusion, adverse events were manageable and the majority of patients did not require hospitalization.


Subject(s)
Lymphoma, Follicular , Receptors, Antigen, T-Cell , Adult , Antigens, CD19 , Cytokines , Humans , Immunotherapy, Adoptive , Lymphoma, Follicular/drug therapy , Retrospective Studies
6.
Front Immunol ; 13: 893247, 2022.
Article in English | MEDLINE | ID: covidwho-1957158

ABSTRACT

TCR-epitope pair binding is the key component for T cell regulation. The ability to predict whether a given pair binds is fundamental to understanding the underlying biology of the binding mechanism as well as developing T-cell mediated immunotherapy approaches. The advent of large-scale public databases containing TCR-epitope binding pairs enabled the recent development of computational prediction methods for TCR-epitope binding. However, the number of epitopes reported along with binding TCRs is far too small, resulting in poor out-of-sample performance for unseen epitopes. In order to address this issue, we present our model ATM-TCR which uses a multi-head self-attention mechanism to capture biological contextual information and improve generalization performance. Additionally, we present a novel application of the attention map from our model to improve out-of-sample performance by demonstrating on recent SARS-CoV-2 data.


Subject(s)
Epitopes, T-Lymphocyte , Receptors, Antigen, T-Cell , Computational Biology , Epitopes, T-Lymphocyte/metabolism , Humans , Protein Binding , Receptors, Antigen, T-Cell/metabolism , SARS-CoV-2
7.
Blood Cells Mol Dis ; 97: 102678, 2022 11.
Article in English | MEDLINE | ID: covidwho-1944311

ABSTRACT

The T cell-mediated immune responses associated with asymptomatic infection (AS) of SARS-CoV-2 remain largely unknown. The diversity of T-cell receptor (TCR) repertoire is essential for generating effective immunity against viral infections in T cell response. Here, we performed the single-cell TCR sequencing of the PBMC samples from five AS subjects, 33 symptomatic COVID-19 patients and eleven healthy controls to investigate the size and the diversity of TCR repertoire. We subsequently analyzed the TCR repertoire diversity, the V and J gene segment deference, and the dominant combination of αß VJ gene pairing among these three study groups. Notably, we revealed significant TCR preference in the AS group, including the skewed usage of TRAV1-2-J33-TRBV6-4-J2-2 and TRAV1-2-J33-TRBV6-1-J2-3. Our findings may shed new light on understanding the immunopathogenesis of COVID-19 and help identify optimal TCRs for development of novel therapeutic strategies against SARS-CoV-2 infection.


Subject(s)
COVID-19 , Humans , Leukocytes, Mononuclear , Receptors, Antigen, T-Cell/genetics , SARS-CoV-2 , T-Lymphocytes
8.
Cell Calcium ; 101: 102524, 2022 01.
Article in English | MEDLINE | ID: covidwho-1914206

ABSTRACT

A recent publication proposes that T cell receptor activation elicits formation of the Ca2+ releasing messenger NAADP from NAADPH, catalysed by the NADPH oxidase DUOX. This is in contrast to the hitherto prevailing view that CD38 is critical for NAADP formation. Is it time to reassess the role of CD38?


Subject(s)
Calcium , Membrane Glycoproteins , ADP-ribosyl Cyclase 1/metabolism , Calcium/metabolism , Calcium Signaling , Membrane Glycoproteins/metabolism , NADP/metabolism , Receptors, Antigen, T-Cell
9.
J Hum Genet ; 67(7): 411-419, 2022 Jul.
Article in English | MEDLINE | ID: covidwho-1908140

ABSTRACT

Since severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) was first reported in China in December 2019, various variants have been identified in different areas of the world such as United Kingdom (alpha), South Africa (beta and omicron), Brazil (gamma), and India (delta). Some of SARS-CoV-2 variants, each of which is characterized by a unique mutation(s) in spike protein, are concerned due to their high infectivity and the capability to escape from neutralizing antibodies elicited by vaccinations. To identify peptide epitopes that are derived from SARS-CoV-2 viral proteins and possibly induce CD8+ T cell immunity, we investigated SARS-CoV-2-derived peptides that are likely to bind to major histocompatibility complex (MHC) class I molecules. We identified a total of 15 peptides that bind to human leukocyte antigen (HLA)-A*24:02, HLA-A*02:01, or HLA-A*02:06, and possibly induce cytotoxic T lymphocytes (CTLs); thirteen of them corresponded to ORF1ab polyprotein, one peptide to spike protein and the remaining one to membrane glycoprotein. CD8+ T cells that recognize these peptides were detected in peripheral blood samples in three individuals recovered from COVID-19 as well as non-infected individuals. Since most of these peptides are commonly conserved among other coronaviruses including SARS-CoV and/or MERS-CoV, these might be useful to maintain T cell responses to coronaviruses that are pandemic at present and will become the future threat. We could define pairs of TRA and TRB sequences of nine CTL clones that recognize SARS-CoV-2-derived peptides. We might use these SARS-CoV-2-derived peptide-reactive TCR sequences for investigating the history of SARS-CoV-2 infection.


Subject(s)
COVID-19 , SARS-CoV-2 , CD8-Positive T-Lymphocytes , Epitopes, T-Lymphocyte/genetics , HLA-A Antigens , Humans , Peptides/chemistry , Receptors, Antigen, T-Cell , Spike Glycoprotein, Coronavirus/genetics , T-Lymphocytes, Cytotoxic
10.
Sci Rep ; 12(1): 9995, 2022 06 15.
Article in English | MEDLINE | ID: covidwho-1900651

ABSTRACT

Interactions between the gut microbiota and the immune system may be involved in vaccine and infection responses. In the present study, we studied the interactions between caecal microbiota composition and parameters describing the immune response in six experimental inbred chicken lines harboring different MHC haplotypes. Animals were challenge-infected with the infectious bronchitis virus (IBV), and half of them were previously vaccinated against this pathogen. We explored to what extent the gut microbiota composition and the genetic line could be related to the immune response, evaluated through flow cytometry. To do so, we characterized the caecal bacterial communities with a 16S rRNA gene amplicon sequencing approach performed one week after the IBV infectious challenge. We observed significant effects of both the vaccination and the genetic line on the microbiota after the challenge infection with IBV, with a lower bacterial richness in vaccinated chickens. We also observed dissimilar caecal community profiles among the different lines, and between the vaccinated and non-vaccinated animals. The effect of vaccination was similar in all the lines, with a reduced abundance of OTU from the Ruminococcacea UCG-014 and Faecalibacterium genera, and an increased abundance of OTU from the Eisenbergiella genus. The main association between the caecal microbiota and the immune phenotypes involved TCRϒδ expression on TCRϒδ+ T cells. This phenotype was negatively associated with OTU from the Escherichia-Shigella genus that were also less abundant in the lines with the highest responses to the vaccine. We proved that the caecal microbiota composition is associated with the IBV vaccine response level in inbred chicken lines, and that the TCRϒδ+ T cells (judged by TCRϒδ expression) may be an important component involved in this interaction, especially with bacteria from the Escherichia-Shigella genus. We hypothesized that bacteria from the Escherichia-Shigella genus increased the systemic level of bacterial lipid antigens, which subsequently mitigated poultry γδ T cells.


Subject(s)
Coronavirus Infections , Infectious bronchitis virus , Microbiota , Poultry Diseases , Viral Vaccines , Animals , Chickens , Coronavirus Infections/prevention & control , Coronavirus Infections/veterinary , Poultry Diseases/genetics , Poultry Diseases/prevention & control , RNA, Ribosomal, 16S/genetics , Receptors, Antigen, T-Cell , Vaccination/veterinary
11.
Nat Immunol ; 23(5): 649-651, 2022 05.
Article in English | MEDLINE | ID: covidwho-1873527
12.
Methods Mol Biol ; 2453: 379-421, 2022.
Article in English | MEDLINE | ID: covidwho-1872265

ABSTRACT

Single-cell adaptive immune receptor repertoire sequencing (scAIRR-seq) offers the possibility to access the nucleotide sequences of paired receptor chains from T-cell receptors (TCR) or B-cell receptors (BCR ). Here we describe two protocols and the downstream bioinformatic approaches that facilitate the integrated analysis of paired T-cell receptor (TR ) alpha/beta (TRA /TRB ) AIRR-seq, RNA sequencing (RNAseq), immunophenotyping, and antigen-binding information. To illustrate the methodologies with a use case, we describe how to identify, characterize, and track SARS-CoV-2-specific T cells over multiple time points following infection with the virus. The first method allows the analysis of pools of memory CD8+ cells, identifying expansions and contractions of clones of interest. The second method allows the study of rare or antigen-specific cells and allows studying their changes over time.


Subject(s)
COVID-19 , Single-Cell Analysis , Base Sequence , Humans , Receptors, Antigen, T-Cell/genetics , SARS-CoV-2/genetics , Single-Cell Analysis/methods , Transcriptome
13.
Cell Rep ; 39(11): 110952, 2022 Jun 14.
Article in English | MEDLINE | ID: covidwho-1866957

ABSTRACT

Sequence homology between SARS-CoV-2 and common-cold human coronaviruses (HCoVs) raises the possibility that memory responses to prior HCoV infection can affect T cell response in COVID-19. We studied T cell responses to SARS-CoV-2 and HCoVs in convalescent COVID-19 donors and identified a highly conserved SARS-CoV-2 sequence, S811-831, with overlapping epitopes presented by common MHC class II proteins HLA-DQ5 and HLA-DP4. These epitopes are recognized by low-abundance CD4 T cells from convalescent COVID-19 donors, mRNA vaccine recipients, and uninfected donors. TCR sequencing revealed a diverse repertoire with public TCRs. T cell cross-reactivity is driven by the high conservation across human and animal coronaviruses of T cell contact residues in both HLA-DQ5 and HLA-DP4 binding frames, with distinct patterns of HCoV cross-reactivity explained by MHC class II binding preferences and substitutions at secondary TCR contact sites. These data highlight S811-831 as a highly conserved CD4 T cell epitope broadly recognized across human populations.


Subject(s)
COVID-19 , SARS-CoV-2 , Alleles , CD4-Positive T-Lymphocytes , COVID-19 Vaccines , Epitopes, T-Lymphocyte , HLA Antigens , Humans , Receptors, Antigen, T-Cell , mRNA Vaccines
14.
Cancer Cell ; 40(7): 738-753.e5, 2022 07 11.
Article in English | MEDLINE | ID: covidwho-1866941

ABSTRACT

How immune dysregulation affects recovery from COVID-19 infection in patients with cancer remains unclear. We analyzed cellular and humoral immune responses in 103 patients with prior COVID-19 infection, more than 20% of whom had delayed viral clearance. Delayed clearance was associated with loss of antibodies to nucleocapsid and spike proteins with a compensatory increase in functional T cell responses. High-dimensional analysis of peripheral blood samples demonstrated increased CD8+ effector T cell differentiation and a broad but poorly converged COVID-specific T cell receptor (TCR) repertoire in patients with prolonged disease. Conversely, patients with a CD4+ dominant immunophenotype had a lower incidence of prolonged disease and exhibited a deep and highly select COVID-associated TCR repertoire, consistent with effective viral clearance and development of T cell memory. These results highlight the importance of B cells and CD4+ T cells in promoting durable SARS-CoV-2 clearance and the significance of coordinated cellular and humoral immunity for long-term disease control.


Subject(s)
COVID-19 , CD4-Positive T-Lymphocytes , CD8-Positive T-Lymphocytes , Humans , Immunity, Cellular , Immunity, Humoral , Immunologic Memory , Receptors, Antigen, T-Cell , SARS-CoV-2
15.
J Immunol ; 208(12): 2675-2685, 2022 06 15.
Article in English | MEDLINE | ID: covidwho-1863025

ABSTRACT

The adaptive immune receptor repertoire consists of the entire set of an individual's BCRs and TCRs and is believed to contain a record of prior immune responses and the potential for future immunity. Analyses of TCR repertoires via deep learning (DL) methods have successfully diagnosed cancers and infectious diseases, including coronavirus disease 2019. However, few studies have used DL to analyze BCR repertoires. In this study, we collected IgG H chain Ab repertoires from 276 healthy control subjects and 326 patients with various infections. We then extracted a comprehensive feature set consisting of 10 subsets of repertoire-level features and 160 sequence-level features and tested whether these features can distinguish between infected individuals and healthy control subjects. Finally, we developed an ensemble DL model, namely, DL method for infection diagnosis (https://github.com/chenyuan0510/DeepID), and used this model to differentiate between the infected and healthy individuals. Four subsets of repertoire-level features and four sequence-level features were selected because of their excellent predictive performance. The DL method for infection diagnosis outperformed traditional machine learning methods in distinguishing between healthy and infected samples (area under the curve = 0.9883) and achieved a multiclassification accuracy of 0.9104. We also observed differences between the healthy and infected groups in V genes usage, clonal expansion, the complexity of reads within clone, the physical properties in the α region, and the local flexibility of the CDR3 amino acid sequence. Our results suggest that the Ab repertoire is a promising biomarker for the diagnosis of various infections.


Subject(s)
COVID-19 , Deep Learning , Amino Acid Sequence , COVID-19/diagnosis , Humans , Receptors, Antigen, T-Cell
17.
Front Immunol ; 13: 880190, 2022.
Article in English | MEDLINE | ID: covidwho-1809409

ABSTRACT

T-cells specifically bind antigens to induce adaptive immune responses using highly specific molecular recognition, and a diverse T-cell repertoire with expansion of antigen-specific clones can indicate robust immune responses after infection or vaccination. For patients with inflammatory bowel disease (IBD), a spectrum of chronic intestinal inflammatory diseases usually requiring immunomodulatory treatment, the T-cell response has not been well characterized. Understanding the patient factors that result in strong vaccination responses is critical to guiding vaccination schedules and identifying mechanisms of T-cell responses in IBD and other immune-mediated conditions. Here we used T-cell receptor sequencing to show that T-cell responses in an IBD cohort were influenced by demographic and immune factors, relative to a control cohort of health care workers (HCWs). Subjects were sampled at the time of SARS-CoV-2 vaccination, and longitudinally afterwards; TCR Vß gene repertoires were sequenced and analyzed for COVID-19-specific clones. We observed significant differences in the overall strength of the T-cell response by age and vaccine type. We further stratified the T-cell response into Class-I- and Class-II-specific responses, showing that Ad26.COV2.S vector vaccine induced Class-I-biased T-cell responses, whereas mRNA vaccine types led to different responses, with mRNA-1273 vaccine inducing a more Class-I-deficient T-cell response compared to BNT162b2. Finally, we showed that these T-cell patterns were consistent with antibody levels from the same patients. Our results account for the surprising success of vaccination in nominally immuno-compromised IBD patients, while suggesting that a subset of IBD patients prone to deficiencies in T-cell response may warrant enhanced booster protocols.


Subject(s)
COVID-19 , Inflammatory Bowel Diseases , 2019-nCoV Vaccine mRNA-1273 , Ad26COVS1 , BNT162 Vaccine , COVID-19 Vaccines , Humans , Immunity, Humoral , Receptors, Antigen, T-Cell/genetics , SARS-CoV-2 , Vaccines, Synthetic , mRNA Vaccines
18.
JCI Insight ; 7(10)2022 05 23.
Article in English | MEDLINE | ID: covidwho-1794308

ABSTRACT

BACKGROUNDMeasuring the immune response to SARS-CoV-2 enables assessment of past infection and protective immunity. SARS-CoV-2 infection induces humoral and T cell responses, but these responses vary with disease severity and individual characteristics.METHODSA T cell receptor (TCR) immunosequencing assay was conducted using small-volume blood samples from 302 individuals recovered from COVID-19. Correlations between the magnitude of the T cell response and neutralizing antibody (nAb) titers or indicators of disease severity were evaluated. Sensitivity of T cell testing was assessed and compared with serologic testing.RESULTSSARS-CoV-2-specific T cell responses were significantly correlated with nAb titers and clinical indicators of disease severity, including hospitalization, fever, and difficulty breathing. Despite modest declines in depth and breadth of T cell responses during convalescence, high sensitivity was observed until at least 6 months after infection, with overall sensitivity ~5% greater than serology tests for identifying prior SARS-CoV-2 infection. Improved performance of T cell testing was most apparent in recovered, nonhospitalized individuals sampled > 150 days after initial illness, suggesting greater sensitivity than serology at later time points and in individuals with less severe disease. T cell testing identified SARS-CoV-2 infection in 68% (55 of 81) of samples with undetectable nAb titers (<1:40) and in 37% (13 of 35) of samples classified as negative by 3 antibody assays.CONCLUSIONThese results support TCR-based testing as a scalable, reliable measure of past SARS-CoV-2 infection with clinical value beyond serology.TRIAL REGISTRATIONSpecimens were accrued under trial NCT04338360 accessible at clinicaltrials.gov.FUNDINGThis work was funded by Adaptive Biotechnologies, Frederick National Laboratory for Cancer Research, NIAID, Fred Hutchinson Joel Meyers Endowment, Fast Grants, and American Society for Transplantation and Cell Therapy.


Subject(s)
COVID-19 , Antibodies, Neutralizing , Antibodies, Viral , Humans , Receptors, Antigen, T-Cell/genetics , SARS-CoV-2 , Severity of Illness Index , United States
19.
JCI Insight ; 7(10)2022 05 23.
Article in English | MEDLINE | ID: covidwho-1794307

ABSTRACT

T cells play a prominent role in orchestrating the immune response to viral diseases, but their role in the clinical presentation and subsequent immunity to SARS-CoV-2 infection remains poorly understood. As part of a population-based survey of the municipality of Vo', Italy, conducted after the initial SARS-CoV-2 outbreak, we sampled the T cell receptor (TCR) repertoires of the population 2 months after the initial PCR survey and followed up positive cases 9 and 15 months later. At 2 months, we found that 97.0% (98 of 101) of cases had elevated levels of TCRs associated with SARS-CoV-2. T cell frequency (depth) was increased in individuals with more severe disease. Both depth and diversity (breadth) of the TCR repertoire were positively associated with neutralizing antibody titers, driven mostly by CD4+ T cells directed against spike protein. At the later time points, detection of these TCRs remained high, with 90.7% (78 of 96) and 86.2% (25 of 29) of individuals having detectable signal at 9 and 15 months, respectively. Forty-three individuals were vaccinated by month 15 and showed a significant increase in TCRs directed against spike protein. Taken together, these results demonstrate the central role of T cells in mounting an immune defense against SARS-CoV-2 that persists out to 15 months.


Subject(s)
COVID-19 , CD4-Positive T-Lymphocytes , Humans , Receptors, Antigen, T-Cell/metabolism , SARS-CoV-2 , Spike Glycoprotein, Coronavirus
20.
Nat Immunol ; 23(5): 781-790, 2022 05.
Article in English | MEDLINE | ID: covidwho-1778617

ABSTRACT

Although mRNA vaccine efficacy against severe coronavirus disease 2019 remains high, variant emergence has prompted booster immunizations. However, the effects of repeated exposures to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigens on memory T cells are poorly understood. Here, we utilize major histocompatibility complex multimers with single-cell RNA sequencing to profile SARS-CoV-2-responsive T cells ex vivo from humans with one, two or three antigen exposures, including vaccination, primary infection and breakthrough infection. Exposure order determined the distribution between spike-specific and non-spike-specific responses, with vaccination after infection leading to expansion of spike-specific T cells and differentiation to CCR7-CD45RA+ effectors. In contrast, individuals after breakthrough infection mount vigorous non-spike-specific responses. Analysis of over 4,000 epitope-specific T cell antigen receptor (TCR) sequences demonstrates that all exposures elicit diverse repertoires characterized by shared TCR motifs, confirmed by monoclonal TCR characterization, with no evidence for repertoire narrowing from repeated exposure. Our findings suggest that breakthrough infections diversify the T cell memory repertoire and current vaccination protocols continue to expand and differentiate spike-specific memory.


Subject(s)
COVID-19 , SARS-CoV-2 , CD8-Positive T-Lymphocytes , Humans , Phenotype , Receptors, Antigen, T-Cell/genetics , Spike Glycoprotein, Coronavirus/genetics , Vaccines, Synthetic , mRNA Vaccines
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