scholarly journals Persistent memory CD4+ and CD8+ T-cell responses in recovered severe acute respiratory syndrome (SARS) patients to SARS coronavirus M antigen

2007 ◽  
Vol 88 (10) ◽  
pp. 2740-2748 ◽  
Author(s):  
Litao Yang ◽  
Hui Peng ◽  
Zhaoling Zhu ◽  
Gang Li ◽  
Zitong Huang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Severe Acute Respiratory Syndrome ◽  
Flow Cytometric Analysis ◽  
Memory Cell ◽  
T Cell Response ◽  
M Protein ◽  
Effector Memory ◽  
Cell Phenotype ◽  
Human T Cell

The membrane (M) protein of severe acute respiratory syndrome coronavirus (SARS-CoV) is a major glycoprotein with multiple biological functions. In this study, we found that memory T cells against M protein were persistent in recovered SARS patients by detecting gamma interferon (IFN-γ) production using ELISA and ELISpot assays. Flow cytometric analysis showed that both CD4+ and CD8+ T cells were involved in cellular responses to SARS-CoV M antigen. Furthermore, memory CD8+ T cells displayed an effector memory cell phenotype expressing CD45RO− CCR7− CD62L−. In contrast, the majority of IFN-γ + CD4+ T cells were central memory cells with the expression of CD45RO+ CCR7+ CD62L−. The epitope screening from 30 synthetic overlapping peptides that cover the entire SARS-CoV M protein identified four human T-cell immunodominant peptides, p21-44, p65-91, p117-140 and p200-220. All four immunodominant peptides could elicit cellular immunity with a predominance of CD8+ T-cell response. This data may have important implication for developing SARS vaccines.

scholarly journals Short-Lived Effector CD8 T Cells Induced by Genetically Attenuated Malaria Parasite Vaccination Express CD11c

2013 ◽  
Vol 81 (11) ◽  
pp. 4171-4181 ◽  
Author(s):  
Laura A. Cooney ◽  
Megha Gupta ◽  
Sunil Thomas ◽  
Sebastian Mikolajczak ◽  
Kimberly Y. Choi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Inflammatory Cytokines ◽  
Plasmodium Yoelii ◽  
T Cell Response ◽  
Parasite Development ◽  
Effector Memory ◽  
Cell Phenotype ◽  
Effector Cells ◽  
Ifn Γ

ABSTRACTVaccination with a single dose of genetically attenuated malaria parasites can induce sterile protection against sporozoite challenge in the rodentPlasmodium yoeliimodel. Protection is dependent on CD8+T cells, involves perforin and gamma interferon (IFN-γ), and is correlated with the expansion of effector memory CD8+T cells in the liver. Here, we have further characterized vaccine-induced changes in the CD8+T cell phenotype and demonstrated significant upregulation of CD11c on CD3+CD8b+T cells in the liver, spleen, and peripheral blood. CD11c+CD8+T cells are predominantly CD11ahiCD44hiCD62L−, indicative of antigen-experienced effector cells. Followingin vitrorestimulation with malaria-infected hepatocytes, CD11c+CD8+T cells expressed inflammatory cytokines and cytotoxicity markers, including IFN-γ, tumor necrosis factor alpha (TNF-α), interleukin-2 (IL-2), perforin, and CD107a. CD11c−CD8+T cells, on the other hand, expressed negligible amounts of all inflammatory cytokines and cytotoxicity markers tested, indicating that CD11c marks multifunctional effector CD8+T cells. Coculture of CD11c+, but not CD11c−, CD8+T cells with sporozoite-infected primary hepatocytes significantly inhibited liver-stage parasite development. Tetramer staining for the immunodominant circumsporozoite protein (CSP)-specific CD8+T cell epitope demonstrated that approximately two-thirds of CSP-specific cells expressed CD11c at the peak of the CD11c+CD8+T cell response, but CD11c expression was lost as the CD8+T cells entered the memory phase. Further analyses showed that CD11c+CD8+T cells are primarily KLRG1+CD127−terminal effectors, whereas all KLRG1−CD127+memory precursor effector cells are CD11c−CD8+T cells. Together, these results suggest that CD11c marks a subset of highly inflammatory, short-lived, antigen-specific effector cells, which may play an important role in eliminating infected hepatocytes.

scholarly journals Modified Vaccinia Ankara–Vectored Vaccine Expressing Nucleoprotein and Matrix Protein 1 (M1) Activates Mucosal M1-Specific T-Cell Immunity and Tissue-Resident Memory T Cells in Human Nasopharynx-Associated Lymphoid Tissue

2019 ◽  
Vol 222 (5) ◽  
pp. 807-819 ◽  
Author(s):  
Suttida Puksuriwong ◽  
Muhammad S Ahmed ◽  
Ravi Sharma ◽  
Madhan Krishnan ◽  
Sam Leong ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
Lymphoid Tissue ◽  
Matrix Protein ◽  
T Cell Response ◽  
Effector Memory ◽  
Cell Phenotype ◽  
Memory T Cell ◽  
Cell Immunity

Abstract Background Increasing evidence supports a critical role of CD8+ T-cell immunity against influenza. Activation of mucosal CD8+ T cells, particularly tissue-resident memory T (TRM) cells recognizing conserved epitopes would mediate rapid and broad protection. Matrix protein 1 (M1) is a well-conserved internal protein. Methods We studied the capacity of modified vaccinia Ankara (MVA)–vectored vaccine expressing nucleoprotein (NP) and M1 (MVA-NP+M1) to activate M1-specific CD8+ T-cell response, including TRM cells, in nasopharynx-associated lymphoid tissue from children and adults. Results After MVA-NP+M1 stimulation, M1 was abundantly expressed in adenotonsillar epithelial cells and B cells. MVA-NP+M1 activated a marked interferon γ–secreting T-cell response to M1 peptides. Using tetramer staining, we showed the vaccine activated a marked increase in M158–66 peptide-specific CD8+ T cells in tonsillar mononuclear cells of HLA-matched individuals. We also demonstrated MVA-NP+M1 activated a substantial increase in TRM cells exhibiting effector memory T-cell phenotype. On recall antigen recognition, M1-specific T cells rapidly undergo cytotoxic degranulation, release granzyme B and proinflammatory cytokines, leading to target cell killing. Conclusions MVA-NP+M1 elicits a substantial M1-specific T-cell response, including TRM cells, in nasopharynx-associated lymphoid tissue, demonstrating its strong capacity to expand memory T-cell pool exhibiting effector memory T-cell phenotype, therefore offering great potential for rapid and broad protection against influenza reinfection.

scholarly journals Quantitative analysis of the CD8 + T–cell response to readily eliminated and persistent viruses

2000 ◽  
Vol 355 (1400) ◽  
pp. 1093-1101 ◽  
Author(s):  
P. C. Doherty ◽  
J. M. Riberdy ◽  
G. T. Belz
Keyword(s):  
T Cells ◽  
T Cell ◽  
Influenza A ◽  
Flow Cytometric Analysis ◽  
T Cell Response ◽  
Basic Question ◽  
Cell Mediated Immunity ◽  
Specific Response ◽  
Turnover Rates

The recent development of techniques for the direct staining of peptide–specific CD8 + T cells has revolutionized the analysis of cell–mediated immunity (CMI) in virus infections. This approach has been used to quantify the acute and long–term consequences of infecting laboratory mice with the readily eliminated influenza A viruses (fluA) and a persistent γherpesvirus (γHV). It is now, for the first time, possible to work with real numbers in the analysis of CD8 + T CMI, and to define various characteristics of the responding lymphocytes both by direct flow cytometric analysis and by sorting for further in vitro manipulation. Relatively little has yet been done from the latter aspect, though we are rapidly accumulating a mass of numerical data. The acute, antigen–driven phases of the fluA and γHV–specific response look rather similar, but CD8 + T–cell numbers are maintained in the long term at a higher ‘set point’ in the persistent infection. Similarly, these ‘memory’ T cells continue to divide at a much greater rate in the γHV–infected mice. New insights have also been generated on the nature of the recall response following secondary challenge in both experimental systems, and the extent of protection conferred by large numbers of virus–specific CD8 + T cells has been determined. However, there are still many parameters that have received little attention, partly because they are difficult to measure. These include the rate of antigen–specific CD8 + T–cell loss, the extent of the lymphocyte ‘diaspora’ to other tissues, and the diversity of functional characteristics, turnover rates, clonal life spans and recirculation profiles. The basic question for immunologists remains how we reconcile the extraordinary plasticity of the immune system with the mechanisms that maintain a stable milieu interieur. This new capacity to quantify CD8 + T–cell responses in readily manipulated mouse models has obvious potential for illuminating homeostatic control, particularly if the experimental approaches to the problem are designed in the context of appropriate predictive models.

scholarly journals Human Immunodeficiency Virus Type 1 (HIV-1)-Specific CD8+ TEMRA Cells in Early Infection Are Linked to Control of HIV-1 Viremia and Predict the Subsequent Viral Load Set Point

2007 ◽  
Vol 81 (11) ◽  
pp. 5759-5765 ◽  
Author(s):  
John W. Northfield ◽  
Christopher P. Loo ◽  
Jason D. Barbour ◽  
Gerald Spotts ◽  
Frederick M. Hecht ◽  
...  
Keyword(s):  
T Cells ◽  
Viral Load ◽  
T Cell ◽  
Absolute Number ◽  
T Cell Response ◽  
Effector Memory ◽  
Set Point ◽  
Effector Memory T Cells ◽  
Viral Load Set Point ◽  
Hiv 1

ABSTRACT CD8+ T cells are believed to play an important role in the control of human immunodeficiency virus type 1 (HIV-1) infection. However, despite intensive efforts, it has not been possible to consistently link the overall magnitude of the CD8+ T-cell response with control of HIV-1. Here, we have investigated the association of different CD8+ memory T-cell subsets responding to HIV-1 in early infection with future control of HIV-1 viremia. Our results demonstrate that both a larger proportion and an absolute number of HIV-1-specific CD8+ CCR7− CD45RA+ effector memory T cells (TEMRA cells) were associated with a lower future viral load set point. In contrast, a larger absolute number of HIV-1-specific CD8+ CCR7− CD45RA− effector memory T cells (TEM) was not related to the viral load set point. Overall, the findings suggest that CD8+ TEMRA cells have superior antiviral activity and indicate that both qualitative and quantitative aspects of the CD8+ T-cell response need to be considered when defining the characteristics of protective immunity to HIV-1.

Combination cancer immunotherapy targeting PD-1 and GITR can rescue CD8+T cell dysfunction and maintain memory phenotype

2018 ◽  
Vol 3 (29) ◽  
pp. eaat7061 ◽  
Author(s):  
Bei Wang ◽  
Wen Zhang ◽  
Vladimir Jankovic ◽  
Jacquelynn Golubov ◽  
Patrick Poon ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Programmed Cell Death ◽  
Cancer Immunotherapy ◽  
Effector Memory ◽  
Cell Phenotype ◽  
Checkpoint Inhibition ◽  
Cell Dysfunction ◽  
T Cell Dysfunction

Most patients with cancer do not develop durable antitumor responses after programmed cell death protein 1 (PD-1) or programmed cell death ligand 1(PD-L1) checkpoint inhibition monotherapy because of an ephemeral reversal of T cell dysfunction and failure to promote long-lasting immunological T cell memory. Activating costimulatory pathways to induce stronger T cell activation may improve the efficacy of checkpoint inhibition and lead to durable antitumor responses. We performed single-cell RNA sequencing of more than 2000 tumor-infiltrating CD8+T cells in mice receiving both PD-1 and GITR (glucocorticoid-induced tumor necrosis factor receptor–related protein) antibodies and found that this combination synergistically enhanced the effector function of expanded CD8+T cells by restoring the balance of key homeostatic regulators CD226 and T cell immunoreceptor with Ig and ITIM domains (TIGIT), leading to a robust survival benefit. Combination therapy decreased CD8+T cell dysfunction and induced a highly proliferative precursor effector memory T cell phenotype in a CD226-dependent manner. PD-1 inhibition rescued CD226 activity by preventing PD-1–Src homology region 2 (SHP2) dephosphophorylation of the CD226 intracellular domain, whereas GITR agonism decreased TIGIT expression. Unmasking the molecular pathways driving durable antitumor responses will be essential to the development of rational approaches to optimizing cancer immunotherapy.

scholarly journals 193 The Achilles VELOSTM Process 2 boosts the dose of highly functional clonal neoantigen-reactive T cells for precision personalized cell therapies

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A205-A205
Author(s):  
Eleni Kotsiou ◽  
Joe Robinson ◽  
Amber Rogers ◽  
Daisy Melandri ◽  
Amy Baker ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Manufacturing Process ◽  
Intracellular Cytokine Staining ◽  
Flow Cytometric Analysis ◽  
Effector Memory ◽  
Potency Assay ◽  
Link Type ◽  
Median Process ◽  
Specific Expansion

BackgroundAdoptive transfer of ex-vivo expanded tumor-infiltrating lymphocytes (TIL) has shown promise in the clinic. However, the non-specific expansion of TIL and the lack of understanding of the active component of TIL has resulted in poor correlation between clinical response and dose as well as poor understanding of response and resistance mechanisms. The VELOSTM manufacturing process generates a precision and personalized treatment modality by targeting clonal neoantigens with the incorporation of an antigen-specific expansion step to enrich the product for these specificities. Achilles has developed a second generation manufacturing process (VELOSTM Process 2) to boost the neoantigen-reactive cell dose while maintaining key qualitative features associated with function. Here we report the in-depth characterization of clonal neoantigen-reactive T cells (cNeT) products expanded using the two VELOSTM processes.MethodsMatched tumors and peripheral blood from patients undergoing routine surgery were obtained from patients with primary NSCLC or metastatic melanoma (NCT03517917). TIL were expanded from tumor fragments and peptide pools corresponding to the clonal mutations identified using the PELEUSTM bioinformatics platform were synthesized. cNeT were expanded by co-culture of TIL with peptide-pulsed autologous dendritic cells, with an optimized cytokine cocktail and co-stimulation for Process 2. Neoantigen reactivity was assessed using our proprietary potency assay with peptide pool re-challenge followed by intracellular cytokine staining. Single peptide reactivities were identified using ELISPOT and flow cytometric analysis for in-depth phenotyping of cNeT was performed.ResultsCD3+ T cells displayed higher fold expansion in Process 2 (median 77.4) compared to Process 1 (median 3.8)(n=5). Both processes showed similar CD3+ T cell content (median Process 1=91.3%, Process 2=96.9% n=5) and contained both CD4+ and CD8+ T cells showing reactivity to clonal neoantigens. Proportion of cells responding to neoantigen re-challenge was similar across both processes (median Process 1=19.9% and Process 2=18.2%) leading to higher reactive dose when coupled with higher T cell doses in Process 2. Phenotypically T cells were predominantly effector memory for both processes and Process 2 had lower frequencies of terminally differentiated T cells.ConclusionsAchilles’ proprietary potency assay enables the optimization of new processes that deliver high cNeT doses to patients by detecting the active drug component. We have generated proof of concept data that supports the transfer of the VELOSTM Process 2 to clinical manufacture for two first-in-human studies for the treatment of solid cancers.Ethics ApprovalThe samples for the study were collected under an ethically approved protocol (NCT03517917)

scholarly journals Combination of a Sindbis-SARS-CoV-2 spike vaccine and αOX40 antibody elicits protective immunity against SARS-CoV-2 induced disease and potentiates long-term SARS-CoV-2-specific humoral and T-cell immunity

2021 ◽  
Author(s):  
Antonella Scaglione ◽  
Silvana Opp ◽  
Alicia Hurtado ◽  
Christine Pampeno ◽  
Ziyan Lin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Protective Immunity ◽  
T Cell Response ◽  
Spike Protein ◽  
Effector Memory ◽  
World Population ◽  
Vaccine Platform ◽  
Vaccine Approach

The COVID-19 pandemic caused by the coronavirus SARS-CoV-2 is a major global public threat. Currently, a worldwide effort has been mounted to generate billions of effective SARS-CoV-2 vaccine doses to immunize the world population at record speeds. However, there is still demand for alternative effective vaccines that rapidly confer long-term protection and rely upon cost-effective, easily scaled-up manufacturing. Here, we present a Sindbis alphavirus vector (SV), transiently expressing the SARS-CoV-2 spike protein (SV.Spike), combined with the OX40 immunostimulatory antibody (OX40) as a novel, highly effective vaccine approach. We show that SV.Spike plus αOX40 elicits long-lasting neutralizing antibodies and a vigorous T cell response in mice. Protein binding, immunohistochemical and cellular infection assays all show that vaccinated mice sera inhibits spike functions. Immunophenotyping, RNA Seq transcriptome profiles and metabolic analysis indicate a reprogramming of T cells in vaccinated mice. Activated T cells were found to mobilize to lung tissue. Most importantly, SV.Spike plus αOX40 provided robust immune protection against infection with authentic coronavirus in transgenic mice expressing the human ACE2 receptor (hACE2-Tg). Finally, our immunization strategy induced strong effector memory response, potentiating protective immunity against re-exposure to SARS-CoV-2 spike protein. Our results show the potential of a new Sindbis virus-based vaccine platform to counteract waning immune response that can be used as a new candidate to combat SARS-CoV-2. Given the strong T cell responses elicited, our vaccine is likely to be effective against variants that are proving challenging, as well as, serve as a platform to develop a broader spectrum pancoronavirus vaccine. Similarly, the vaccine approach is likely to be applicable to other pathogens.

scholarly journals Vaccination against RhoC induces long-lasting immune responses in patients with prostate cancer: results from a phase I/II clinical trial

2020 ◽  
Vol 8 (2) ◽  
pp. e001157
Author(s):  
Juliane Schuhmacher ◽  
Sonja Heidu ◽  
Torben Balchen ◽  
Jennifer Rebecca Richardson ◽  
Camilla Schmeltz ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Phase I ◽  
Cell Response ◽  
Small Gtpase ◽  
T Cell Response ◽  
Effector Memory ◽  
Tolerability Profile

BackgroundPeptide-based vaccination is a rational option for immunotherapy of prostate cancer. In this first-in-man phase I/II study, we assessed the safety, tolerability and immunological impact of a synthetic long peptide vaccine targeting Ras homolog gene family member C (RhoC) in patients with prostate cancer. RhoC is a small GTPase overexpressed in advanced solid cancers, metastases and cancer stem cells.MethodsTwenty-two patients who had previously undergone radical prostatectomy received subcutaneous injections of 0.1 mg of a single RhoC-derived 20mer peptide emulsified in Montanide ISA-51 every 2 weeks for the first six times, then five times every 4 weeks for a total treatment time of 30 weeks. The drug safety and vaccine-specific immune responses were assessed during treatment and thereafter within a 13-month follow-up period. Serum level of prostate-specific antigen was measured up to 26 months postvaccination.ResultsMost patients (18 of 21 evaluable) developed a strong CD4 T cell response against the vaccine, which lasted at least 10 months following the last vaccination. Three promiscuouslypresented HLA-class II epitopes were identified. Vaccine-specific CD4 T cells were polyfunctional and effector memory T cells that stably expressed PD-1 (CD279) and OX-40 (CD134), but not LAG-3 (CD223). One CD8 T cell response was detected in addition. The vaccine was well tolerated and no treatment-related adverse events of grade ≥3 were observed.ConclusionTargeting of RhoC induced a potent and long-lasting T cell immunity in the majority of the patients. The study demonstrates an excellent safety and tolerability profile. Vaccination against RhoC could potentially delay or prevent tumor recurrence and metastasis formation.Trial registration numberNCT03199872.

scholarly journals Protective Immunity against Experimental Pulmonary Cryptococcosis in T Cell-Depleted Mice

2011 ◽  
Vol 18 (5) ◽  
pp. 717-723 ◽  
Author(s):  
Karen L. Wozniak ◽  
Mattie L. Young ◽  
Floyd L. Wormley
Keyword(s):  
T Cells ◽  
T Cell ◽  
Protective Immunity ◽  
Effector Memory ◽  
Cell Phenotype ◽  
Cell Mediated Immunity ◽  
Wild Type ◽  
Pulmonary Cryptococcosis ◽  
Content Type ◽  
Immunocompetent Mice

ABSTRACTIndividuals with defects in T cell-mediated immunity (CMI) are highly susceptible to infection withCryptococcus neoformans. The purpose of these studies was to determine if protection against experimental pulmonary cryptococcosis can be generated in T cell-deficient hosts. BALB/c mice were depleted of CD4+and/or CD8+T cells or given an isotype control antibody prior to vaccination with aC. neoformansstrain, designated H99γ, previously shown to induce protection againstC. neoformansinfection in immunocompetent mice. Mice depleted of CD4+or CD8+T cells, but not both subsets, survived an acute pulmonary infection withC. neoformansstrain H99γ and a subsequent second challenge with wild-typeC. neoformansstrain H99. We observed a significant increase in the percentage of CD4+and CD8+T cells expressing the activation marker CD69 in the lungs of mice immunized withC. neoformansstrain H99γ prior to a secondary challenge with wild-type cryptococci. CD4+T cells within the lungs of immunized mice also appeared to acquire a predominantly activated effector memory cell phenotype (CD69+CD44+CCR7−CD45RB−CD62L−) following a second pulmonary challenge with wild-typeC. neoformans, compared to CD4+T cells from naïve mice. Lastly, immunization of immunocompetent mice withC. neoformansstrain H99γ prior to depletion of CD4+and/or CD8+T cells resulted in significant protection against a second challenge with wild-typeC. neoformans. Our studies demonstrate that protective immunity against pulmonary cryptococcosis can be generated in immunosuppressed hosts, thus supporting the development of cryptococcal vaccines.

scholarly journals Characterization of local and circulating bovine γδ T cell responses to respiratory BCG vaccination

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Mariana Guerra-Maupome ◽  
Jodi L. McGill
Keyword(s):  
T Cells ◽  
T Cell ◽  
Γδ T Cells ◽  
T Cell Responses ◽  
Memory Cell ◽  
Effector Memory ◽  
Γδ T Cell ◽  
Respiratory Mucosa ◽  
Bcg Vaccination ◽  
Cell Responses

Abstract The Mycobacterium bovis Bacillus Calmette-Guerin (BCG) vaccine is administered parenterally to infants and young children to prevent tuberculosis (TB) infection. However, the protection induced by BCG is highly variable and the vaccine does not prevent pulmonary TB, the most common form of the illness. Until improved TB vaccines are available, it is crucial to use BCG in a manner which ensures optimal vaccine performance. Immunization directly to the respiratory mucosa has been shown to promote greater protection from TB in animal models. γδ T cells play a major role in host defense at mucosal sites and are known to respond robustly to mycobacterial infection. Their positioning in the respiratory mucosa ensures their engagement in the response to aerosolized TB vaccination. However, our understanding of the effect of respiratory BCG vaccination on γδ T cell responses in the lung is unknown. In this study, we used a calf model to investigate the immunogenicity of aerosol BCG vaccination, and the phenotypic profile of peripheral and mucosal γδ T cells responding to vaccination. We observed robust local and systemic M. bovis-specific IFN-γ and IL-17 production by both γδ and CD4 T cells. Importantly, BCG vaccination induced effector and memory cell differentiation of γδ T cells in both the lower airways and peripheral blood, with accumulation of a large proportion of effector memory γδ T cells in both compartments. Our results demonstrate the potential of the neonatal calf model to evaluate TB vaccine candidates that are to be administered via the respiratory tract, and suggest that aerosol immunization is a promising strategy for engaging γδ T cells in vaccine-induced immunity against TB.

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