scholarly journals Metabolic control of T cell immune response through glycans in inflammatory bowel disease

2018 ◽  
Vol 115 (20) ◽  
pp. E4651-E4660 ◽  
Author(s):  
Ana M. Dias ◽  
Alexandra Correia ◽  
Márcia S. Pereira ◽  
Catarina R. Almeida ◽  
Inês Alves ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Disease Severity ◽  
Ex Vivo ◽  
Cell Activity ◽  
Cell Receptor ◽  
T Cell Response ◽  
Cell Immune Response ◽  
T Helper 1 ◽  
Glycosylation Pathway

Mucosal T lymphocytes from patients with ulcerative colitis (UC) were previously shown to display a deficiency in branched N-glycosylation associated with disease severity. However, whether this glycosylation pathway shapes the course of the T cell response constituting a targeted-specific mechanism in UC remains largely unknown. In this study, we demonstrated that metabolic supplementation of ex vivo mucosal T cells from patients with active UC with N-acetylglucosamine (GlcNAc) resulted in enhancement of branched N-glycosylation in the T cell receptor (TCR), leading to suppression of T cell growth, inhibition of the T helper 1 (Th1)/Th17 immune response, and controlled T cell activity. We further demonstrated that mouse models displaying a deficiency in the branched N-glycosylation pathway (MGAT5−/−, MGAT5+/−) exhibited increased susceptibility to severe forms of colitis and early-onset disease. Importantly, the treatment of these mice with GlcNAc reduced disease severity and suppressed disease progression due to a controlled T cell-mediated immune response at the intestinal mucosa. In conclusion, our human ex vivo and preclinical results demonstrate the targeted-specific immunomodulatory properties of this simple glycan, proposing a therapeutic approach for patients with UC.

scholarly journals Analysis of TCR Repertoire by High-Throughput Sequencing Indicates the Feature of T Cell Immune Response after SARS-CoV-2 Infection

Cells ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 68
Author(s):  
Yifan Wang ◽  
Fugang Duan ◽  
Zhu Zhu ◽  
Meng Yu ◽  
Xiaodong Jia ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
High Throughput Sequencing ◽  
Cell Receptor ◽  
T Cell Response ◽  
Patient Specific ◽  
Cell Immune Response ◽  
Tcr Repertoire

Coronavirus disease 2019 (COVID-19) is a global infectious disease caused by the SARS-CoV-2 coronavirus. T cells play an essential role in the body’s fighting against the virus invasion, and the T cell receptor (TCR) is crucial in T cell-mediated virus recognition and clearance. However, little has been known about the features of T cell response in convalescent COVID-19 patients. In this study, using 5′RACE technology and PacBio sequencing, we analyzed the TCR repertoire of COVID-19 patients after recovery for 2 weeks and 6 months compared with the healthy donors. The TCR clustering and CDR3 annotation were exploited to discover groups of patient-specific TCR clonotypes with potential SARS-CoV-2 antigen specificities. We first identified CD4+ and CD8+ T cell clones with certain clonal expansion after infection, and then observed the preferential recombination usage of V(D) J gene segments in CD4+ and CD8+ T cells of COVID-19 patients with different convalescent stages. More important, the TRBV6-5-TRBD2-TRBJ2-7 combination with high frequency was shared between CD4+ T and CD8+ T cells of different COVID-19 patients. Finally, we found the dominant characteristic motifs of the CDR3 sequence between recovered COVID-19 and healthy control. Our study provides novel insights on TCR in COVID-19 with different convalescent phases, contributing to our understanding of the immune response induced by SARS-CoV-2.

scholarly journals Checkpoint blockade accelerates a novel switch from an NKT-driven TNFα response toward a T cell driven IFN-γ response within the tumor microenvironment

2021 ◽  
Vol 9 (6) ◽  
pp. e002269
Author(s):  
Shota Aoyama ◽  
Ryosuke Nakagawa ◽  
Satoshi Nemoto ◽  
Patricio Perez-Villarroel ◽  
James J Mulé ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Ex Vivo ◽  
T Cell Response ◽  
Effector Function ◽  
Checkpoint Blockade ◽  
Necrosis Factor Alpha ◽  
Ifn Γ

BackgroundThe temporal response to checkpoint blockade (CB) is incompletely understood. Here, we profiled the tumor infiltrating lymphocyte (TIL) landscape in response to combination checkpoint blockade at two distinct timepoints of solid tumor growth.MethodsC57BL/6 mice bearing subcutaneous MC38 tumors were treated with anti-PD-1 and/or anti-CTLA-4 antibodies. At 11 or 21 days, TIL phenotype and effector function were analyzed in excised tumor digests using high parameter flow cytometry. The contributions of major TIL populations toward overall response were then assessed using ex vivo cytotoxicity and in vivo tumor growth assays.ResultsThe distribution and effector function among 37 distinct TIL populations shifted dramatically between early and late MC38 growth. At 11 days, the immune response was dominated by Tumor necrosis factor alpha (TNFα)-producing NKT, representing over half of all TIL. These were accompanied by modest frequencies of natural killer (NK), CD4+, or CD8+ T cells, producing low levels of IFN-γ. At 21 days, NKT populations were reduced to a combined 20% of TIL, giving way to increased NK, CD4+, and CD8+ T cells, with increased IFN-γ production. Treatment with CB accelerated this switch. At day 11, CB reduced NKT to less than 20% of all TIL, downregulated TNFα across NKT and CD4+ T cell populations, increased CD4+ and CD8+ TIL frequencies, and significantly upregulated IFN-γ production. Degranulation was largely associated with NK and NKT TIL. Blockade of H-2kb and/or CD1d during ex vivo cytotoxicity assays revealed NKT has limited direct cytotoxicity against parent MC38. However, forced CD1d overexpression in MC38 cells significantly diminished tumor growth, suggesting NKT TIL exerts indirect control over MC38 growth.ConclusionsDespite an indirect benefit of early NKT activity, CB accelerates a switch from TNFα, NKT-driven immune response toward an IFN-γ driven CD4+/CD8+ T cell response in MC38 tumors. These results uncover a novel NKT/T cell switch that may be a key feature of CB response in CD1d+ tumors.

Expression of MG7-Ag in patients with gastric cancer correlates with weaker T cell immune response and more proinflammatory cytokine secretion

2006 ◽  
Vol 84 (2) ◽  
pp. 135-141 ◽  
Author(s):  
Xiaoyin Zhang ◽  
Liu Hong ◽  
W Y Chan ◽  
Taidong Qiao ◽  
Baojun Chen ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Immune Response ◽  
T Cell ◽  
Gastric Carcinoma ◽  
T Cell Receptor ◽  
Proinflammatory Cytokine ◽  
Cell Receptor ◽  
Cytokine Secretion ◽  
Cell Immune Response ◽  
Rt Pcr

MG7-Ag is a human gastric-carcinoma-associated antigen with a high specificity. So far it is remained unclear whether MG7-Ag is correlated with the in vivo cellular immune response of patients with gastric cancer. In this study, we detected the expression of the T cell receptor (TCR) repertoire of T cell subpopulations and cytokines in tumor-infiltrating lymphocytes (TIL), peripheral blood lymphocytes (PBL), and residue benign mucosal lymphocytes (NML) of patients with gastric cancer using semiquantitative RT-PCR. Our data showed that the expanded clones in CD8+ NML and TIL and CD4+ NML and PBL in MG7-Ag-positive patients were significantly fewer than those of MG7-Ag-negative patients (p = 0.0360; p = 0.0026; p = 0.0065 p = 0.0109, respectively). The levels of IL-8 in CD8+ TIL and TNF in CD4+ TIL from the MG7-Ag-positive group were significantly higher than those from the MG7-Ag-negative group (p = 0.0302; p = 0.0177, respectively). Taken together, the results demonstrated a weaker T cell immune response and more proinflammatory cytokine secretion in MG7-Ag-positive patients with gastric cancer than in MG7-Ag-negative ones. This likely contributes to the poor prognosis in MG7-Ag-positive gastric-cancer patients.Key words: gastric carcinoma, tumor-associated antigen, T cell receptor repertoire, cytokine, RT-PCR.

scholarly journals The T cell receptor repertoire reflects the dynamics of the immune response to vaccination

2021 ◽  
Author(s):  
Kevin Mohammed ◽  
Austin Meadows ◽  
Sandra Hatem ◽  
Viviana Simon ◽  
Anitha D Jayaprakash ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Influenza Vaccine ◽  
T Cell Receptor ◽  
Cell Response ◽  
Cell Receptor ◽  
Physical Symptoms ◽  
T Cell Response ◽  
Tcr Repertoire

Early, high-resolution metrics are needed to ascertain the immune response to vaccinations. The T cell receptor (TCR), a heterodimer of one α and one β chain, is a promising target, with the complete TCR repertoire reflecting the T cells present in an individual. To this end, we developed Tseek, an unbiased and accurate method for profiling the TCR repertoire by sequencing the TCR α and β chains and developing a suite of tools for repertoire analysis. An added advantage is the ability to non-invasively analyze T cells in peripheral blood mononuclear cells (PBMCs). Tseek and the analytical suite were used to explore the T cell response to both the COVID-19 mRNA vaccine (n=9) and the seasonal inactivated Influenza vaccine (n=5) at several time points. Neutralizing antibody titers were also measured in the covid vaccine samples. The COVID-19 vaccine elicited a broad T cell response involving multiple expanded clones, whereas the Influenza vaccine elicited a narrower response involving fewer clones. Many distinct T cell clones responded at each time point, over a month, providing temporal details lacking in the antibody measurements, especially before the antibodies are detectable. In individuals recovered from a SARS-CoV-2 infection, the first vaccine dose elicited a robust T cell response, while the second dose elicited a comparatively weaker response, indicating a saturation of the response. The physical symptoms experienced by the recipients immediately following the vaccinations were not indicative of the TCR/antibody responses, while a weak TCR response seemed to presage a weak antibody response. We also found that the TCR repertoire acts as an individual fingerprint: donors of blood samples taken years apart could be identified solely based upon their TCR repertoire, hinting at other surprising uses the TCR repertoire may have. These results demonstrate the promise of TCR repertoire sequencing as an early and sensitive measure of the adaptive immune response to vaccination, which can help improve immunogen selection and optimize vaccine dosage and spacing between doses.

Tumor and systemic immune responses to preoperative (pre-op) cryoablation (cryo) plus immune therapy with ipilimumab (ipi) in early-stage breast cancer (ESBC).

2014 ◽  
Vol 32 (26_suppl) ◽  
pp. 64-64 ◽  
Author(s):  
David B. Page ◽  
Jianda Yuan ◽  
Arielle Ginsberg ◽  
Zhiwan Dong ◽  
Phillip Wong ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Pilot Study ◽  
Early Stage ◽  
Immune Therapy ◽  
Cell Activity ◽  
Standard Of Care ◽  
Cell Receptor ◽  
Hormone Receptor Positive

64 Background: In mice, tumor cryo plus immunologic checkpoint blockade generates tumor antigen release, proliferation of tumor-specific T-cells, and enhanced survival. We previously demonstrated in a pilot study that pre-op cryo+ipi is well tolerated in women with ESBC and did not delay standard of care surgical resection. Here, we analyze pilot study tissue and blood to explore immune response. Methods: 18 ESBC patients (pts) were treated with preop cryo (n=6), single-dose ipi 10mg/kg (n=6), or cryo+ipi (n=6). As a potential surrogate for tumor immunogenicity, baseline T-cell tumor infiltrating lymphocyte (TIL) density was evaluated by T-cell receptor quantitative DNA sequencing. We explored the systemic immune response to cryo and/or ipi using previously described laboratory measures including inducible costimulator (ICOS, a marker of activated CD4+ T-cells) and plasma interferon gamma (IFNγ, a cytokine associated with T-cell activity). Results: Of the 18 study pts, 13 pts had hormone receptor-positive (HR+) disease, 2 pts had HER2+ disease (both treated with ipi alone) and 3 pts had triple-negative (TN) disease (1 ipi alone and 2 cryo/ipi). Baseline TIL density was highly variable overall (range 2-30%), but higher in HER2+ and TN pts (median 15%) compared with HR+ pts (median 5%). Sustained >2-fold elevations in ICOS and IFNγ were observed in the majority of cryo+ipi pts 30 days following treatment (ICOS: 5/6 pts; IFNγ: 4/6 pts), but in the minority of ipi pts (ICOS: 2/6 pts; IFNγ: 2/6 pts) or cryo pts (ICOS: 0/6 pts; IFNγ: 0/6 pts). Sustained ICOS and IFNγ elevations were observed regardless of baseline TIL density. Conclusions: Cryo+ipi was more likely to induce systemic immune activation compared to cryo or ipi alone. These potentially beneficial immune effects were observed in both HR+ and HR- subtypes, as well as in tumors with low or high baseline TIL density. These data support further studies of cryo+ipi in ESBC across HR+ and HR- subtypes, as well as in tumors that do not appear immunogenic at baseline.

scholarly journals A new concept on anti-SARS-CoV-2 vaccines: strong CD8+ T-cell immune response in both spleen and lung induced in mice by endogenously engineered extracellular vesicles

2020 ◽  
Author(s):  
Flavia Ferrantelli ◽  
Chiara Chiozzini ◽  
Francesco Manfredi ◽  
Patrizia Leone ◽  
Maurizio Federico
Keyword(s):  
T Cells ◽  
T Cell ◽  
Extracellular Vesicles ◽  
High Efficiency ◽  
Ex Vivo ◽  
T Cell Response ◽  
Cell Immune Response ◽  
Cell Immunity ◽  
Dna Vectors

AbstractSevere acute respiratory syndrome coronavirus (SARS-CoV)-2 is spreading rapidly in the absence of validated tools to control the growing epidemic besides social distancing and masks. Many efforts are ongoing for the development of vaccines against SARS-CoV-2 since there is an imminent need to develop effective interventions for controlling and preventing SARS-CoV-2 spread. Essentially all vaccines in most advanced phases are based on the induction of antibody response against either whole or part of spike (S) protein. Differently, we developed an original strategy to induce CD8+ T cytotoxic lymphocyte (CTL) immunity based on in vivo engineering of extracellular vesicles (EVs). We exploited this technology with the aim to identify a clinical candidate defined as DNA vectors expressing SARS-CoV-2 antigens inducing a robust CD8+ T-cell response. This is a new vaccination approach employing a DNA expression vector encoding a biologically inactive HIV-1 Nef protein (Nefmut) showing an unusually high efficiency of incorporation into EVs even when foreign polypeptides are fused to its C-terminus. Nanovesicles containing Nefmut-fused antigens released by muscle cells are internalized by antigen-presenting cells leading to cross-presentation of the associated antigens thereby priming of antigen-specific CD8+ T-cells. To apply this technology to a design of anti-SARS-CoV-2 vaccine, we recovered DNA vectors expressing the products of fusion between Nefmut and four viral antigens, namely N- and C-terminal moieties of S (referred to as S1 and S2), M, and N. All fusion products are efficiently uploaded in EVs. When the respective DNA vectors were injected in mice, a strong antigen-specific CD8+ T cell immunity was generated. Most important, high levels of virus-specific CD8+ T cells were found in bronchoalveolar lavages of immunized mice. Co-injection of DNA vectors expressing the diverse SARS-CoV-2 antigens resulted in additive immune responses in both spleen and lung. EVs engineered with SARS-CoV-2 antigens proved immunogenic also in the human system through cross-priming assays carried out with ex vivo human cells. Hence, DNA vectors expressing Nefmut-based fusion proteins can be proposed as anti-SARS-CoV-2 vaccine candidates.

scholarly journals Brd4 Regulates the Homeostasis of CD8+ T-Lymphocytes and Their Proliferation in Response to Antigen Stimulation

2021 ◽  
Vol 12 ◽  
Author(s):  
Zhilin Peng ◽  
Yiwen Zhang ◽  
Xiancai Ma ◽  
Mo Zhou ◽  
Shiyu Wu ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
T Cell Response ◽  
Cell Immune Response ◽  
Type I ◽  
T Cell Homeostasis ◽  
Cell Homeostasis ◽  
Antigen Stimulation

CD8+ T cells are major components of adaptive immunity and confer robust protective cellular immunity, which requires adequate T-cell numbers, targeted migration, and efficient T-cell proliferation. Altered CD8+ T-cell homeostasis and impaired proliferation result in dysfunctional immune response to infection or tumorigenesis. However, intrinsic factors controlling CD8+ T-cell homeostasis and immunity remain largely elusive. Here, we demonstrate the prominent role of Brd4 on CD8+ T cell homeostasis and immune response. By upregulating Myc and GLUT1 expression, Brd4 facilitates glucose uptake and energy production in mitochondria, subsequently supporting naïve CD8+ T-cell survival. Besides, Brd4 promotes the trafficking of naïve CD8+ T cells partially through maintaining the expression of homing receptors (CD62L and LFA-1). Furthermore, Brd4 is required for CD8+ T cell response to antigen stimulation, as Brd4 deficiency leads to a severe defect in clonal expansion and terminal differentiation by decreasing glycolysis. Importantly, as JQ1, a pan-BRD inhibitor, severely dampens CD8+ T-cell immune response, its usage as an anti-tumor agent or latency-reversing agent for human immunodeficiency virus type I (HIV-1) should be more cautious. Collectively, our study identifies a previously-unexpected role of Brd4 in the metabolic regulation of CD8+ T cell-mediated immune surveillance and also provides a potential immunomodulation target.

scholarly journals Antigen-specific T-cell receptor signatures of cytomegalovirus infection

2018 ◽  
Author(s):  
Alina Huth ◽  
Xiaoling Liang ◽  
Stefan Krebs ◽  
Helmut Blum ◽  
Andreas Moosmann
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Response ◽  
Ex Vivo ◽  
Cell Receptor ◽  
T Cell Response ◽  
The Body ◽  
T Cell Epitopes ◽  
Virus Reactivation

AbstractCytomegalovirus (CMV) is a prevalent human pathogen. The virus cannot be eliminated from the body, but is kept in check by CMV-specific T cells. Patients with an insufficient T-cell response, such as transplant recipients, are at high risk of developing CMV disease. However, the CMV-specific T-cell repertoire is complex, and is not yet clear which T cells protect best against virus reactivation and disease. Here we present a highly resolved characterization of CMV-specific CD8+ T cells based on enrichment by specific peptide stimulation and mRNA sequencing of their T-cell receptor β chains (TCRβ). Our analysis included recently identified T-cell epitopes restricted through HLA-C, whose presentation is resistant to viral immunomodulation, and well-studied HLA-B-restricted epitopes. In 8 healthy virus carriers, we identified a total of 1052 CMV-specific TCRβ chains. HLA-C-restricted, CMV-specific TCRβ clonotypes theex vivoT-cell response, and contributed the highest-frequency clonotype of the entire repertoire in 2 of 8 donors. We analyzed sharing and similarity of CMV-specific TCRβ sequences and identified 63 public or related sequences belonging to 17 public TCRβ families. In our cohort and in an independent cohort of 352 donors, the cumulative frequency of these public TCRβ family members was a highly discriminatory indicator of carrying both CMV infection and the relevant HLA type. Based on these findings, we propose CMV-specific TCRβ signatures as a biomarker for an antiviral T-cell response to identify patients in need of treatment and to guide future development of immunotherapy.

scholarly journals Cellular Immune Responses to BNT162b2 mRNA COVID-19 Vaccine in Patients with Chronic Lymphocytic Leukemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 638-638
Author(s):  
Gilad Itchaki ◽  
Lior Rokach ◽  
Ohad Benjamini ◽  
Osnat Bairey ◽  
Adi Sabag ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Cell Response ◽  
Research Funding ◽  
T Cell Response ◽  
Lymphocytic Leukemia ◽  
Cell Immune Response ◽  
P Value ◽  
Igg Antibodies ◽  
Cellular Immune

Abstract Background: Patients with chronic lymphocytic leukemia (CLL) are known to have a suboptimal immune response of both humoral and cellular arms. Recently, a BNT162b2 mRNA COVID-19 vaccine was introduced with a high efficacy of 95% in immunocompetent individuals. Approximately half of the patients with CLL fail to mount a humoral response to the vaccine, as detected by anti-spike antibodies. Currently, there is no data available regarding T-cell immune responses following the vaccine of these patients. Aim of the study: To investigate T-cell response determined by interferon gamma (IFNγ) secretion in patients with CLL following BNT162b mRNA Covid-19 vaccine, in comparison with serologic response. Methods: CLL patients from 3 medical centers in Israel were included in the study. All patients received two 30-μg doses of BNT162b2 vaccine (Pfizer), administered intramuscularly 3 weeks apart. For evaluation of SARS-CoV-2 Spike-specific T-cell responses, blood samples were stimulated ex-vivo with Spike protein and secreted IFNγ was quantified (ELISA DuoSet, R&D Systems, Minneapolis, Minnesota, USA). T-cell immune response was considered to be positive for values above 25 pg/ml of Spike-specific response. T-cell subpopulations were characterized by flow cytometry (CD3, CD4, CD8). Anti-spike antibody tests were performed using the Architect AdviseDx SARS-CoV-2 IgG II (Abbot, Lake Forest, Illinois, USA). Statistical analysis was performed using Mann-Whitney test for continuous variables while the Wald Chi-square test was used for comparing categorical variables. Results: 83 patients with CLL were tested for T-cell response. Blood samples were collected after a median time of 139 days post administration of the second dose of vaccine (IQ range 134-152). Out of 83 patients, 68 were eligible for the analysis (with positive internal control). Median age of the cohort was 68 years (56-72); and 44 (65%) were males. 19 (28%) patients were treatment-naïve, most of whom were Binet stage A or B. 31 (46%) patients were on therapy: 17 with a BTK-inhibitor, and 13 with a venetoclax-based regimen. 29 (42%) patients were previously treated with anti-CD20, 13 of whom in the 12 months period prior to vaccination. T cell immune response to the vaccine was evident in 22 (32%) patients. CIRS Score>6 and specifically hypertension were statistically significantly associated with a lower T-cell response (univariate analysis, p-value<0.05). Variables that were associated with the development of T-cell response were presence of del(13q), IgM ≥ 40 mg/dL, and IgA ≥ 80 mg/dL (p-value 0.05-0.1). There was no significant difference with regards to age, gender, other CLL-specific prognostic markers, treatment, and T-cell subpopulation distribution according to flow cytometry (Table 1). The presence of T-cell response highly correlated with both the detection of anti-spike IgG antibodies following the second dose (p=0.0239) and at the time of T-cell testing (n=66, p=0.048, Table 2). While 50% of patients who tested positive for anti-spike IgG antibodies also developed positive T-cell response, only 17% of patients who did not develop T-cell response, tested positive for anti-spike antibodies. Importantly, 24% of the patients who tested negative for anti-spike IgG antibodies, developed positive T cell response. Moreover, the level of the T-cell response (log transformed) correlated linearly with (log transformed) anti-spike IgG titer (adjusted r=0.26 and p =0.026 according to Pearson correlation, Figure 1). Conclusion: We show that cellular immune response to the BNT162b2 mRNA COVID-19 vaccine, is blunted in most CLL patients and that there is a correlation between T-cell response and serologic response to the vaccine. These results need to be validated in a larger cohort. Figure 1 Figure 1. Disclosures Itchaki: AbbVie: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Benjamini: Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Tadmor: AbbVie: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding.

scholarly journals T-cell receptor sequencing identifies prior SARS-CoV-2 infection and correlates with neutralizing antibody titers and disease severity

2021 ◽  
Author(s):  
Rebecca Elyanow ◽  
Thomas M. Snyder ◽  
Sudeb C. Dalai ◽  
Rachel M. Gittelman ◽  
Jim Boonyaratanakornkit ◽  
...  
Keyword(s):  
T Cell ◽  
Disease Severity ◽  
T Cell Receptor ◽  
Cell Response ◽  
Protective Immunity ◽  
Limit Of Detection ◽  
Neutralizing Antibody ◽  
Cell Receptor ◽  
T Cell Response ◽  
Cell Testing

Measuring the adaptive immune response to SARS-CoV-2 can enable the assessment of past infection as well as protective immunity and the risk of reinfection. While neutralizing antibody (nAb) titers are one measure of protection, such assays are challenging to perform at a large scale and the longevity of the SARS-CoV-2 nAb response is not fully understood. Here, we apply a T-cell receptor (TCR) sequencing assay that can be performed on a small volume standard blood sample to assess the adaptive T-cell response to SARS-CoV-2 infection. Samples were collected from a cohort of 302 individuals recovered from COVID-19 up to 6 months after infection. Previously published findings in this cohort showed that two commercially available SARS-CoV-2 serologic assays correlate well with nAb testing. We demonstrate that the magnitude of the SARS-CoV-2-specific T-cell response strongly correlates with nAb titer, as well as clinical indicators of disease severity including hospitalization, fever, or difficulty breathing. While the depth and breadth of the T-cell response declines during convalescence, the T-cell signal remains well above background with high sensitivity up to at least 6 months following initial infection. Compared to serology tests detecting binding antibodies to SARS-CoV-2 spike and nucleoprotein, the overall sensitivity of the TCR-based assay across the entire cohort and all timepoints was approximately 5% greater for identifying prior SARS-CoV-2 infection. Notably, the improved performance of T-cell testing compared to serology was most apparent in recovered individuals who were not hospitalized and were sampled beyond 150 days of their initial illness, suggesting that antibody testing may have reduced sensitivity in individuals who experienced less severe COVID-19 illness and at later timepoints. Finally, T-cell testing was able to identify SARS-CoV-2 infection in 68% (55/81) of convalescent samples having nAb titers below the lower limit of detection, as well as 37% (13/35) of samples testing negative by all three antibody assays. These results demonstrate the utility of a TCR-based assay as a scalable, reliable measure of past SARS-CoV-2 infection across a spectrum of disease severity. Additionally, the TCR repertoire may be useful as a surrogate for protective immunity with additive clinical value beyond serologic or nAb testing methods.

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