scholarly journals Incomplete recruitment of protective T cells is associated with Trypanosoma cruzi persistence in the mouse colon

2021 ◽  
Author(s):  
Alexander I. Ward ◽  
Michael D. Lewis ◽  
Martin C. Taylor ◽  
John M. Kelly
Keyword(s):  
T Cells ◽  
T Cell ◽  
Trypanosoma Cruzi ◽  
Vaccine Development ◽  
T Cell Response ◽  
Tissue Imaging ◽  
Chronic Infections ◽  
Systematic Analysis ◽  
Mouse Colon ◽  
Parasite Replication

Trypanosoma cruzi is the etiological agent of Chagas disease. Following T cell mediated suppression of the acute phase infection, this intracellular eukaryotic pathogen persists long-term in a limited sub-set of tissues at extremely low-levels. The reasons for this tissue-specific chronicity are not understood. Using a dual bioluminescent:fluorescent reporter strain and highly sensitive tissue imaging that allows experimental infections to be monitored at single-cell resolution, we have undertaken a systematic analysis of the immunological micro-environments of rare parasitized cells in the mouse colon, a key site of persistence. We demonstrate that incomplete recruitment of T cells to a subset of colonic infection foci permits the occurrence of repeated cycles of intracellular parasite replication and differentiation to motile trypomastigotes at a frequency sufficient to perpetuate chronic infections. The life-long persistence of parasites in this tissue site continues despite the presence, at a systemic level, of a highly effective T cell response. Overcoming this low-level dynamic host:parasite equilibrium represents a major challenge for vaccine development.

scholarly journals Incomplete recruitment of protective T cells facilitates Trypanosoma cruzi persistence in the mouse colon

2021 ◽  
Author(s):  
Alexander I. Ward ◽  
Michael D. Lewis ◽  
Martin C. Taylor ◽  
John M. Kelly
Keyword(s):  
T Cells ◽  
T Cell ◽  
Trypanosoma Cruzi ◽  
Vaccine Development ◽  
T Cell Response ◽  
Chronic Infections ◽  
Mouse Colon ◽  
Parasite Replication ◽  
Low Levels ◽  
Tissue Site

AbstractTrypanosoma cruzi is the etiological agent of Chagas disease. Following T cell mediated suppression of the acute phase infection, this intracellular eukaryotic pathogen persists in a limited sub-set of tissues at extremely low-levels. The reasons for this tissue-specific chronicity are not understood. Using a dual bioluminescent:fluorescent reporter strain, which allows experimental infections to be imaged at single-cell resolution, we have characterised the ‘hyper-local’ immunological microenvironment of rare parasitized cells in the mouse colon, a key site of persistence. We demonstrate that incomplete recruitment of T cells to infection foci permits the occurrence of repeated cycles of intracellular parasite replication and differentiation to motile trypomastigotes at a frequency sufficient to perpetuate chronic infections. The life-long persistence of parasites in this tissue site continues despite the presence, at a systemic level, of a highly effective T cell response. Overcoming this low-level dynamic host:parasite equilibrium represents a major challenge for vaccine development.

scholarly journals Functional Avidity: A Measure to Predict the Efficacy of Effector T Cells?

2012 ◽  
Vol 2012 ◽  
pp. 1-14 ◽  
Author(s):  
Selena Viganò ◽  
Daniel T. Utzschneider ◽  
Matthieu Perreau ◽  
Giuseppe Pantaleo ◽  
Dietmar Zehn ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Response ◽  
Cell Populations ◽  
High Avidity ◽  
Chronic Infections ◽  
Functional Avidity ◽  
Cognate Antigen

The functional avidity is determined by exposing T-cell populationsin vitroto different amounts of cognate antigen. T-cells with high functional avidity respond to low antigen doses. Thisin vitromeasure is thought to correlate well with thein vivoeffector capacity of T-cells. We here present the multifaceted factors determining and influencing the functional avidity of T-cells. We outline how changes in the functional avidity can occur over the course of an infection. This process, known as avidity maturation, can occur despite the fact that T-cells express a fixed TCR. Furthermore, examples are provided illustrating the importance of generating T-cell populations that exhibit a high functional avidity when responding to an infection or tumors. Furthermore, we discuss whether criteria based on which we evaluate an effective T-cell response to acute infections can also be applied to chronic infections such as HIV. Finally, we also focus on observations that high-avidity T-cells show higher signs of exhaustion and facilitate the emergence of virus escape variants. The review summarizes our current understanding of how this may occur as well as how T-cells of different functional avidity contribute to antiviral and anti-tumor immunity. Enhancing our knowledge in this field is relevant for tumor immunotherapy and vaccines design.

scholarly journals Longitudinal Analysis of CD8+ T Cells Specific for Structural and Nonstructural Hepatitis B Virus Proteins in Patients with Chronic Hepatitis B: Implications for Immunotherapy

2004 ◽  
Vol 78 (11) ◽  
pp. 5707-5719 ◽  
Author(s):  
George J. M. Webster ◽  
Stephanie Reignat ◽  
David Brown ◽  
Graham S. Ogg ◽  
Louise Jones ◽  
...  
Keyword(s):  
T Cells ◽  
Chronic Hepatitis ◽  
T Cell ◽  
Hepatitis B ◽  
Chronic Hepatitis B ◽  
T Cell Response ◽  
Chronic Infections ◽  
Hbv Replication ◽  
Cell Responses ◽  
B Virus

ABSTRACT The cytotoxic T-cell response in chronic hepatitis B virus (HBV) infection has been described as weak and mono- or oligospecific in comparison to the more robust virus-specific T-cell response present in resolved infection. However, chronic hepatitis B is a heterogeneous disease with markedly variable levels of virus replication and liver disease activity. Here we analyzed (both directly ex vivo and after in vitro stimulation) the HBV-specific CD8 T-cell responses against structural and nonstructural HBV proteins longitudinally in patients with different patterns of chronic infections. We found that the profiles of virus-specific CD8+-T-cell responses during chronic infections are highly heterogeneous and influenced more by the level of HBV replication than by the activity of liver disease. An HBV DNA load of <107 copies/ml appears to be the threshold below which circulating multispecific HBV-specific CD8+ T cells are consistently detected. Furthermore, CD8+ T cells with different specificities are differentially regulated during chronic infections. HBV core-specific CD8+ T cells are associated with viral control, while CD8+ T cells specific for envelope and polymerase epitopes can occasionally be found in the setting of high levels (>107 copies) of HBV replication. These findings have implications for the design of immunotherapy for chronic HBV infections.

scholarly journals Bacterial Protein Secretion Is Required for Priming of CD8+ T Cells Specific for the Mycobacterium tuberculosis Antigen CFP10

2008 ◽  
Vol 76 (9) ◽  
pp. 4199-4205 ◽  
Author(s):  
Joshua S. Woodworth ◽  
Sarah M. Fortune ◽  
Samuel M. Behar
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
T Cell ◽  
Cell Response ◽  
Vaccine Development ◽  
T Cell Response ◽  
Class I Mhc ◽  
Mhc I ◽  
Mycobacterial Antigens

ABSTRACT Mycobacterium tuberculosis infection elicits antigen-specific CD8+ T cells that are required to control disease. It is unknown how the major histocompatibility complex class I (MHC-I) pathway samples mycobacterial antigens. CFP10 and ESAT6 are important virulence factors secreted by M. tuberculosis, and they are immunodominant targets of the human and murine T-cell response. Here, we test the hypothesis that CFP10 secretion by M. tuberculosis is required for the priming of CD8+ T cells in vivo. Our results reveal an explicit dependence upon the bacterial secretion of the CFP10 antigen for the induction of antigen-specific CD8+ T cells in vivo. By using well-defined M. tuberculosis mutants and carefully controlling for virulence, we show that ESX-1 function is required for the priming of CD8+ T cells specific for CFP10. CD4+ and CD8+ T-cell responses to mycobacterial antigens secreted independently of ESX-1 were unaffected, suggesting that ESX-1-dependent phagosomal escape is not required for CD8+ T-cell priming during infection. We propose that the overrepresentation of secreted proteins as dominant targets of the CD8+ T-cell response during M. tuberculosis infection is a consequence of their preferential sampling by the MHC-I pathway. The implications of these findings should be considered in all models of antigen presentation during M. tuberculosis infection and in vaccine development.

scholarly journals Epitope Mapping of the Immunodominant Antigen TB10.4 and the Two Homologous Proteins TB10.3 and TB12.9, Which Constitute a Subfamily of the esat-6 Gene Family

2002 ◽  
Vol 70 (10) ◽  
pp. 5446-5453 ◽  
Author(s):  
Rikke Louise Vinther Skjøt ◽  
Inger Brock ◽  
Sandra M. Arend ◽  
Martin E. Munk ◽  
Michael Theisen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mass Culture ◽  
Vaccine Development ◽  
T Cell Response ◽  
Homologous Proteins ◽  
Gene Encoding ◽  
Immunodominant Antigen ◽  
Human T Cell ◽  
Dominant Epitope

ABSTRACT The human T-cell recognition of the low-molecular-mass culture filtrate antigen TB10.4 was evaluated in detail. The molecule was strongly recognized by T cells isolated from tuberculosis (TB) patients and from BCG-vaccinated donors. The epitopes on TB10.4 were mapped with overlapping peptides and found to be distributed throughout the molecule. The broadest response was found in TB patients, whereas the response in BCG-vaccinated donors was focused mainly toward a dominant epitope located in the N terminus (amino acids 1 to 18). The gene encoding TB10.4 was found to belong to a subfamily within the esat-6 family that consists of the three highly homologous proteins TB10.4, TB10.3, and TB12.9 (Rv0288, Rv3019c, and Rv3017c, respectively). Southern blot analysis combined with database searches revealed that the three members of the TB10.4 family were present only in strains of the Mycobacterium tuberculosis complex, including BCG, and M. kansasii, whereas other atypical mycobacteria had either one (M. avium, M. intracellulare, and M. marinum) or none (M. scrofulaceum, M. fortuitum, and M. szulgai) of the genes. The fine specificity of the T-cell response to the three closely related esat-6 family members was markedly different, with only a few epitopes shared between the molecules. Minimal differences in the amino acid sequence translated into large differences in recognition by T cells and secretion of gamma interferon. In general, the peptides from TB10.4 stimulated the largest responses, but epitopes unique to both TB10.3 and TB12.9 were found. The relevance of the findings for TB vaccine development and as a potential mechanism for immune evasion is discussed.

scholarly journals Influenza A Virus Infection in Pigs Attracts Multifunctional and Cross-Reactive T Cells to the Lung

2016 ◽  
Vol 90 (20) ◽  
pp. 9364-9382 ◽  
Author(s):  
Stephanie C. Talker ◽  
Maria Stadler ◽  
Hanna C. Koinig ◽  
Kerstin H. Mair ◽  
Irene M. Rodríguez-Gómez ◽  
...  
Keyword(s):  
T Cells ◽  
Influenza Virus ◽  
T Cell ◽  
Virus Infection ◽  
Influenza A ◽  
Vaccine Development ◽  
Influenza Virus Infection ◽  
T Cell Response ◽  
Large Animal ◽  
Ifn Γ

ABSTRACTPigs are natural hosts for influenza A viruses and play a critical role in influenza epidemiology. However, little is known about their influenza-evoked T-cell response. We performed a thorough analysis of both the local and systemic T-cell response in influenza virus-infected pigs, addressing kinetics and phenotype as well as multifunctionality (gamma interferon [IFN-γ], tumor necrosis factor alpha [TNF-α], and interleukin-2 [IL-2]) and cross-reactivity. A total of 31 pigs were intratracheally infected with an H1N2 swine influenza A virus (FLUAVsw) and consecutively euthanized. Lungs, tracheobronchial lymph nodes, and blood were sampled during the first 15 days postinfection (p.i.) and at 6 weeks p.i.Ex vivoflow cytometry of lung lymphocytes revealed an increase in proliferating (Ki-67+) CD8+T cells with an early effector phenotype (perforin+CD27+) at day 6 p.i. Low frequencies of influenza virus-specific IFN-γ-producing CD4+and CD8+T cells could be detected in the lung as early as 4 days p.i. On consecutive days, influenza virus-specific CD4+and CD8+T cells produced mainly IFN-γ and/or TNF-α, reaching peak frequencies around day 9 p.i., which were up to 30-fold higher in the lung than in tracheobronchial lymph nodes or blood. At 6 weeks p.i., CD4+and CD8+memory T cells had accumulated in lung tissue. These cells showed diverse cytokine profiles andin vitroreactivity against heterologous influenza virus strains, all of which supports their potential to combat heterologous influenza virus infections in pigs.IMPORTANCEPigs not only are a suitable large-animal model for human influenza virus infection and vaccine development but also play a central role in the emergence of new pandemic strains. Although promising candidate universal vaccines are tested in pigs and local T cells are the major correlate of heterologous control, detailed and targeted analyses of T-cell responses at the site of infection are scarce. With the present study, we provide the first detailed characterization of magnitude, kinetics, and phenotype of specific T cells recruited to the lungs of influenza virus-infected pigs, and we could demonstrate multifunctionality, cross-reactivity, and memory formation of these cells. This, and ensuing work in the pig, will strengthen the position of this species as a large-animal model for human influenza virus infection and will immediately benefit vaccine development for improved control of influenza virus infections in pigs.

scholarly journals Preexisting memory CD4 T cells in naïve individuals confer robust immunity upon vaccination

2020 ◽  
Author(s):  
George Elias ◽  
Pieter Meysman ◽  
Esther Bartholomeus ◽  
Nicolas De Neuter ◽  
Nina Keersmaekers ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
High Throughput Sequencing ◽  
Vaccine Development ◽  
Memory T Cells ◽  
T Cell Response ◽  
Cd4 T Cell ◽  
Vaccine Antigen ◽  
Specific Memory

AbstractAntigen recognition through the T cell receptor (TCR) αβ heterodimer is one of the primary determinants of the adaptive immune response. Vaccines activate naïve T cells with high specificity to expand and differentiate into memory T cells that allow for a quick and robust T cell response upon exposure to the pathogen or re-exposure to the vaccine antigen. This is why the induction of memory T cells is a key feature in vaccine development. However, it has become increasingly evident that antigen-specific memory CD4 and CD8 T cells exist in unexposed antigen-naïve hosts and it is likely that exposure to one antigen might alter the TCR repertoire of memory T cells to a different unrelated antigen. In this study, we utilize high-throughput sequencing to profile the memory CD4 TCRβ repertoire and track vaccine-specific TCRβ clonotypes following the de novo administration of hepatitis B (HepB) vaccine in healthy HepB-naïve individuals and show that vaccinees with preexisting vaccine-specific memory CD4 T cell clonotypes elicited earlier and higher antibody concentrations and mounted a more robust CD4 T cell response to the vaccine. We further identify vaccine-specific TCRβ sequence patterns that can be used to predict which individuals will have an early and more vigorous vaccine-elicited immunity to HepB vaccine. Moreover, we find that an expansion of 4-1BB+ memory TREG is a prominent feature in individuals with delayed and modest vaccine-induced immunity. Our approach shows that modeling pre-vaccination TCRβ repertoire enables prediction of both antibody and CD4 responses to vaccines.

scholarly journals T Cell Immunity Evaluation and Immunodominant Epitope T Cell Receptor Identification of Severe Acute Respiratory Syndrome Coronavirus 2 Spike Glycoprotein in COVID-19 Convalescent Patients

2021 ◽  
Vol 9 ◽  
Author(s):  
Luo Li ◽  
Qian Chen ◽  
Xiaojian Han ◽  
Meiying Shen ◽  
Chao Hu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Severe Acute Respiratory Syndrome ◽  
Vaccine Development ◽  
Cell Receptor ◽  
T Cell Response ◽  
Cell Immunity ◽  
Ifn Γ

A better understanding of the role of T cells in the immune response to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is helpful not only for vaccine development but also for the treatment of COVID-19 patients. In this study, we determined the existence of SARS-CoV-2-specific T cells in the blood of COVID-19 convalescents. Meanwhile, the specific T cell response in the non-RBD region was stronger than in the RBD region. We also found that SARS-CoV-2 S-specific reactive CD4+ T cells exhibited higher frequency than CD8+ T cells in recovered COVID-19 patients, with greater number of corresponding epitopes presented. Importantly, we isolated the SARS-CoV-2-specific CD4+ T cell receptors (TCRs) and inserted the TCRs into allogenic CD4+ T cells. These TCR-T cells can be activated by SARS-CoV-2 spike peptide and produce IFN-γ in vitro. These results might provide valuable information for the development of vaccines and new therapies against COVID-19.

scholarly journals Rapamycin Improves the Response of Effector and Memory CD8+ T Cells Induced by Immunization With ASP2 of Trypanosoma cruzi

2021 ◽  
Vol 11 ◽  
Author(s):  
Barbara Ferri Moraschi ◽  
Isaú Henrique Noronha ◽  
Camila Pontes Ferreira ◽  
Leonardo M. Cariste ◽  
Caroline B. Monteiro ◽  
...  
Keyword(s):  
T Cells ◽  
Trypanosoma Cruzi ◽  
Vaccine Development ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
T Cell Response ◽  
Effector Memory ◽  
Mtor Inhibition ◽  
Beneficial Effects

Deficiency in memory formation and increased immunosenescence are pivotal features of Trypanosoma cruzi infection proposed to play a role in parasite persistence and disease development. The vaccination protocol that consists in a prime with plasmid DNA followed by the boost with a deficient recombinant human adenovirus type 5, both carrying the ASP2 gene of T. cruzi, is a powerful strategy to elicit effector memory CD8+ T-cells against this parasite. In virus infections, the inhibition of mTOR, a kinase involved in several biological processes, improves the response of memory CD8+ T-cells. Therefore, our aim was to assess the role of rapamycin, the pharmacological inhibitor of mTOR, in CD8+ T response against T. cruzi induced by heterologous prime-boost vaccine. For this purpose, C57BL/6 or A/Sn mice were immunized and daily treated with rapamycin for 34 days. CD8+ T-cells response was evaluated by immunophenotyping, intracellular staining, ELISpot assay and in vivo cytotoxicity. In comparison with vehicle-injection, rapamycin administration during immunization enhanced the frequency of ASP2-specific CD8+ T-cells and the percentage of the polyfunctional population, which degranulated (CD107a+) and secreted both interferon gamma (IFNγ) and tumor necrosis factor (TNF). The beneficial effects were long-lasting and could be detected 95 days after priming. Moreover, the effects were detected in mice immunized with ten-fold lower doses of plasmid/adenovirus. Additionally, the highly susceptible to T. cruzi infection A/Sn mice, when immunized with low vaccine doses, treated with rapamycin, and challenged with trypomastigote forms of the Y strain showed a survival rate of 100%, compared with 42% in vehicle-injected group. Trying to shed light on the biological mechanisms involved in these beneficial effects on CD8+ T-cells by mTOR inhibition after immunization, we showed that in vivo proliferation was higher after rapamycin treatment compared with vehicle-injected group. Taken together, our data provide a new approach to vaccine development against intracellular parasites, placing the mTOR inhibitor rapamycin as an adjuvant to improve effective CD8+ T-cell response.

scholarly journals Magnitude and Dynamics of the T-Cell Response to SARS-CoV-2 Infection at Both Individual and Population Levels

2020 ◽  
Author(s):  
Thomas M Snyder ◽  
Rachel M Gittelman ◽  
Mark Klinger ◽  
Damon H May ◽  
Edward J Osborne ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
Vaccine Development ◽  
Human Leukocyte ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Clinical Diagnostics ◽  
Cell Repertoire

T cells are involved in the early identification and clearance of viral infections and also support the development of antibodies by B cells. This central role for T cells makes them a desirable target for assessing the immune response to SARS-CoV-2 infection. Here, we combined two high-throughput immune profiling methods to create a quantitative picture of the T-cell response to SARS-CoV-2. First, at the individual level, we deeply characterized 3 acutely infected and 58 recovered COVID-19 subjects by experimentally mapping their CD8 T-cell response through antigen stimulation to 545 Human Leukocyte Antigen (HLA) class I presented viral peptides (class II data in a forthcoming study). Then, at the population level, we performed T-cell repertoire sequencing on 1,815 samples (from 1,521 COVID-19 subjects) as well as 3,500 controls to identify shared "public" T-cell receptors (TCRs) associated with SARS-CoV-2 infection from both CD8 and CD4 T cells. Collectively, our data reveal that CD8 T-cell responses are often driven by a few immunodominant, HLA-restricted epitopes. As expected, the T-cell response to SARS-CoV-2 peaks about one to two weeks after infection and is detectable for at least several months after recovery. As an application of these data, we trained a classifier to diagnose SARS-CoV-2 infection based solely on TCR sequencing from blood samples, and observed, at 99.8% specificity, high early sensitivity soon after diagnosis (Day 3-7 = 85.1% [95% CI = 79.9-89.7]; Day 8-14 = 94.8% [90.7-98.4]) as well as lasting sensitivity after recovery (Day 29+/convalescent = 95.4% [92.1-98.3]). These results demonstrate an approach to reliably assess the adaptive immune response both soon after viral antigenic exposure (before antibodies are typically detectable) as well as at later time points. This blood-based molecular approach to characterizing the cellular immune response has applications in clinical diagnostics as well as in vaccine development and monitoring.

Sign in / Sign up

Export Citation Format

Share Document