t cell response
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Nano Today ◽  
2022 ◽  
Vol 42 ◽  
pp. 101332
Huaxing Dai ◽  
Qin Fan ◽  
Ziying Fei ◽  
Qingle Ma ◽  
Qianyu Yang ◽  

2022 ◽  
Vardges Tserunyan ◽  
Stacey D Finley

In recent decades, chimeric antigen receptors (CARs) have been successfully used to generate engineered T cells capable of recognizing and eliminating cancer cells. The structure of CARs frequently includes costimulatory domains, which enhance the T cell response upon antigen encounter. However, it is not fully known how the CAR co-stimulatory domains influence T cell activation in the presence of biological variability. In this work, we used mathematical modeling to elucidate how the inclusion of one such co-stimulatory molecule, CD28, impacts the response of a population of engineered T cells under different sources of variability. Particularly, our simulations demonstrate that CD28-bearing CARs mediate a faster and more consistent population response under both target antigen variability and kinetic rate variability. We identify kinetic parameters that have the most impact on mediating cell activation. Finally, based on our findings, we propose that enhancing the catalytic activity of lymphocyte-specific protein tyrosine kinase (LCK) can result in drastically reduced and more consistent response times among heterogeneous CAR T cell populations.

2022 ◽  
Vol 12 ◽  
Carla Usai ◽  
Joseph M. Gibbons ◽  
Corinna Pade ◽  
Wenhao Li ◽  
Sabina R. M. Jacobs ◽  

BackgroundThe presentation of SARS-CoV-2 infection varies from asymptomatic to severe COVID-19. Similarly, high variability in the presence, titre and duration of specific antibodies has been reported. While some host factors determining these differences, such as age and ethnicity have been identified, the underlying molecular mechanisms underpinning these differences remain poorly defined.MethodsWe analysed serum and PBMC from 17 subjects with a previous PCR-confirmed SARS-CoV-2 infection and 10 unexposed volunteers following the first wave of the pandemic, in the UK. Anti-NP IgG and neutralising antibodies were measured, as well as a panel of infection and inflammation related cytokines. The virus-specific T cell response was determined by IFN-γ ELISPOT and flow cytometry after overnight incubation of PBMCs with pools of selected SARS-CoV-2 specific peptides.ResultsSeven of 17 convalescent subjects had undetectable levels of anti-NP IgG, and a positive correlation was shown between anti-NP IgG levels and the titre of neutralising antibodies (IC50). In contrast, a discrepancy was noted between antibody levels and T cell IFN-γ production by ELISpot following stimulation with specific peptides. Among the analysed cytokines, β-NGF and IL-1α levels were significantly different between anti-NP positive and negative subjects, and only β-NGF significantly correlated with anti-NP positivity. Interestingly, CD4+ T cells of anti-NP negative subjects expressed lower amounts of the β-NGF-specific receptor TrkA.ConclusionsOur results suggest that the β-NGF/TrkA signalling pathway is associated with the production of anti-NP specific antibody in mild SARS-CoV-2 infection and the mechanistic regulation of this pathway in COVID-19 requires further investigation.

2022 ◽  
Vol 12 ◽  
Lina Zhang ◽  
Xinyi Shi ◽  
Qing Zhang ◽  
Zhilei Mao ◽  
Xiaoyu Shi ◽  

High-risk human papillomavirus (HPV) infection is the cause of almost all cervical cancers. HPV16 is one of the main risk subtypes. Although screening programs have greatly reduced the prevalence of cervical cancer in developed countries, current diagnostic tests cannot predict if mild lesions may progress into invasive lesions or not. In the current cross-sectional and longitudinal clinical study, we found that the HPV16 E7-specific T cell response in peripheral blood mononuclear cells of HPV16-infected patients is related to HPV16 clearance. It contributes to protecting the squamous interaepithelial lesion (SIL) from further malignant development. Of the HPV16 infected women enrolled (n = 131), 42 had neither intraepithelial lesion nor malignancy (NILM), 33 had low-grade SIL, 39 had high-grade SIL, and 17 had cervical cancer. Only one of 17 (5.9%) cancer patients had a positive HPV16 E7-specific T cell response, dramatically lower than the groups of precancer patients. After one year of follow-up, most women (28/33, 84.8%) with persistent HPV infection did not exhibit a HPV16 E7-specific T cell response. Furthermore, 3 malignantly progressed women, one progressed to high-grade SIL and two progressed to low-grade SIL, were negative to the HPV16 E7-specific T cell response. None of the patients with a positive HPV16 E7-specific T cell response progressed to further deterioration. Our observation suggests that HPV16 E7-specific T cell immunity is significant in viral clearance and contributes in protection against progression to malignancy.

2022 ◽  
Eduard Otto Roos ◽  
William Mwangi ◽  
Wilhelm Gerner ◽  
Ryan Waters ◽  
John A Hammond

This multiplex staining panel was developed to differentiate cattle T cells into conventional (CD4 and CD8) and unconventional (γδ-TCR) subsets as well as their stage of differentiation and activation. The combination of CD45RO and CD62L allows the identification of naïve (TNaïve), central memory (TCM), effector memory (TEM) and terminal effector (TTE) T cells. Activated cattle T cells (TAV) can be identified by the cell surface expression of CD25. This panel was developed using cryopreserved cattle peripheral blood mononuclear cells (PBMCs) and tested on fresh as well as stimulated PBMCs. Therefore, this 8-colour, 10-parameter flow cytometry panel simultaneously identifies cattle TNaïve, TAV, TCM, TEM, TTE and γδ-TCR cells. This panel will improve our ability to examine T cell response to pathogens and vaccines in cattle including the potential to identify previously undescribed subpopulations. Furthermore, this panel can be readily optimised for other bovid species as many of these reagents are likely to cross react.

2022 ◽  
Paolo Corradini ◽  
Chiara Agrati ◽  
Giovanni Apolone ◽  
Alberto Mantovani ◽  
Diana Giannarelli ◽  

Background: Patients with solid or hematological tumors, neurological and immune-inflammatory disorders represent potentially fragile subjects with increased risk to experience severe COVID-19 and inadequate response to SARS-CoV2 vaccination. Methods: We designed a prospective Italian multicentric study to assess humoral and T-cell response to SARS-CoV2 vaccination in patients (n=378) with solid tumors (ST), hematological malignancies (HM), neurological (ND) and immuno-rheumatological diseases (ID). The immunogenicity of primary vaccination schedule and of the booster dose were analyzed. Results: Overall, patient seroconversion rate after two doses was 62.1%. A significant lower rate was observed in HM (52.4%) and ID (51.9%) patients compared to ST (95.6%) and ND (70.7%); a lower median level of antibodies was detected in HM and ID versus the others (p<0.0001). A similar rate of patients with a positive SARS-CoV2 T-cell response was observed in all disease groups, with a higher level observed in the ND group. The booster dose improved humoral responses in all disease groups, although with a lower response in HM patients, while the T-cell response increased similarly in all groups. In the multivariable logistic model, the independent predictors for seroconversion were disease subgroups, type of therapies and age. Notably, the ongoing treatment known to affect the immune system was associated with the worst humoral response to vaccination (p<0.0001), but had no effects on the T-cell responses. Conclusions: Immunosuppressive treatment more than disease type per se is a risk factor for low humoral response after vaccination. The booster dose can improve both humoral and T-cell response.

2022 ◽  
Hassen Kared ◽  
Asia-Sophia Fumika Michaela Wolf ◽  
Amin Alirezaylavasani ◽  
Anthony Ravussin ◽  
Guri Solum ◽  

The new SARS-CoV-2 variant of concern (VOC) Omicron has more than 30 mutations in the receptor binding domain (RBD) of the Spike protein enabling viral escape from antibodies in vaccinated individuals and increased transmissibility. It is unclear how vaccine immunity protects against Omicron infection. Here we show that vaccinated participants at a superspreader event had robust recall response of humoral and pre-existing cellular immunity induced by the vaccines, and an emergent de novo T cell response to non-Spike antigens. We compared cases from a Christmas party where 81 of 110 (74%) developed Omicron breakthrough COVID-19, with Delta breakthrough cases and vaccinated non-infected controls. Omicron cases had significantly increased activated SARS-CoV-2 wild type Spike-specific (vaccine) cytotoxic T cells, activated follicular helper (TFH) cells, functional T cell responses, boosted humoral responses, activated anti-Spike plasmablasts and anti-RBD memory B cells compared to controls. Omicron cases had significantly increased de novo memory T cell responses to non-Spike viral antigens compared to Delta breakthrough cases demonstrating development of broad immunity. The rapid release of Spike and RBD-specific IgG+ B cell plasmablasts and memory B cells into circulation suggested affinity maturation of antibodies and that concerted T and B cell immunity may provide durable broad immunity.

2022 ◽  
Andrea T. Nguyen ◽  
Christopher Szeto ◽  
Demetra S.M. Chatzileontiadou ◽  
Zhen Wei Marcus Tong ◽  
Michael J. Dewar-Oldis ◽  

The >30 mutated residues in the Omicron spike protein have led to its rapid classification as a new SARS-CoV-2 variant of concern. As a result, Omicron may escape from the immune system, decreasing the protection provided by COVID-19 vaccines. Preliminary data shows a weaker neutralizing antibody response to Omicron compared to the ancestral SARS-CoV-2 virus, which can be increased after a booster vaccine. Here, we report that CD8+ T cells can recognize Omicron variant epitopes presented by HLA-A*02:01 in both COVID-19 recovered and vaccinated individuals, even 6 months after infection or vaccination. Additionally, the T cell response was stronger for Omicron variant epitopes after the vaccine booster. Altogether, T cells can recognize Omicron variants, especially in vaccinated individuals after the vaccine booster.

2022 ◽  
Rob Krause ◽  
Thandeka Moyo-Gwete ◽  
Simone Richardson ◽  
Zanele Makhado ◽  
Nelia Manamela ◽  

Abstract Neutralizing antibodies strongly correlate with protection for COVID-19 vaccines, but the corresponding memory B cells that form to protect against future infection are relatively understudied. Here we examine the effect of prior SARS-CoV-2 infection on the magnitude and phenotype of the B cell response to single dose Johnson and Johnson (Ad26.COV2.S) vaccination in South African health care workers. SARS-CoV-2 specific memory responses expand in response to Ad26.COV2.S and are maintained for the study duration (84 days) in all individuals. However, prior infection is associated with a greater frequency of these cells, a more prominent germinal center (GC) response, and increased class switched memory (CSM). These B cell features correlated with both neutralization and antibody-dependent cytotoxicity (ADCC) activity, and with the frequency of SARS-CoV-2 specific circulating T follicular helper cells (cTfh). In addition, the SARS-CoV-2 specific CD8+ T cell response correlated with increased memory B cell lung-homing, which was sustained in the infected group. Finally, although vaccination achieved equivalent B cell activation regardless of infection history, it was negatively impacted by age. These data show that phenotyping the B cell response to vaccination can provide mechanistic insight into the impact of prior infection on GC homing, CSM, cTfh, and neutralization activity. These data can provide early signals and mechanistic understanding to inform studies of vaccine boosting, durability, and co-morbidities.

2022 ◽  
pp. annrheumdis-2021-221508
Jerome Hadjadj ◽  
Delphine Planas ◽  
Amani Ouedrani ◽  
Solene Buffier ◽  
Laure Delage ◽  

ObjectivesThe emergence of strains of SARS-CoV-2 exhibiting increase viral fitness and immune escape potential, such as the Delta variant (B.1.617.2), raises concerns in immunocompromised patients. We aimed to evaluate seroconversion, cross-neutralisation and T-cell responses induced by BNT162b2 in immunocompromised patients with systemic inflammatory diseases.MethodsProspective monocentric study including patients with systemic inflammatory diseases and healthcare immunocompetent workers as controls. Primary endpoints were anti-spike antibodies levels and cross-neutralisation of Alpha and Delta variants after BNT162b2 vaccine. Secondary endpoints were T-cell responses, breakthrough infections and safety.ResultsSixty-four cases and 21 controls not previously infected with SARS-CoV-2 were analysed. Kinetics of anti-spike IgG after BNT162b2 vaccine showed lower and delayed induction in cases, more pronounced with rituximab. Administration of two doses of BNT162b2 generated a neutralising response against Alpha and Delta in 100% of controls, while sera from only one of rituximab-treated patients neutralised Alpha (5%) and none Delta. Other therapeutic regimens induced a partial neutralising activity against Alpha, even lower against Delta. All controls and cases except those treated with methotrexate mounted a SARS-CoV-2 specific T-cell response. Methotrexate abrogated T-cell responses after one dose and dramatically impaired T-cell responses after two doses of BNT162b2. Third dose of vaccine improved immunogenicity in patients with low responses.ConclusionRituximab and methotrexate differentially impact the immunogenicity of BNT162b2, by impairing B-cell and T-cell responses, respectively. Delta fully escapes the humoral response of individuals treated with rituximab. These findings support efforts to improve BNT162b2 immunogenicity in immunocompromised individuals (ClinicalTrials.gov number, NCT04870411).

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