scholarly journals A Prime/Boost PfCS14KM/MVA-sPfCSM Vaccination Protocol Generates Robust CD8+ T Cell and Antibody Responses to Plasmodium falciparum Circumsporozoite Protein and Protects Mice against Malaria

2017 ◽  
Vol 24 (5) ◽  
Author(s):  
Aneesh Vijayan ◽  
Ernesto Mejías-Pérez ◽  
Diego A. Espinosa ◽  
Suresh C. Raman ◽  
Carlos Oscar S. Sorzano ◽  
...  
Keyword(s):  
T Cells ◽  
Plasmodium Falciparum ◽  
T Cell ◽  
Vaccinia Virus ◽  
Disease Onset ◽  
Circumsporozoite Protein ◽  
Effector Memory ◽  
Parasite Line ◽  
Content Type ◽  
Boost Immunization

ABSTRACT Vaccines against the preerythrocytic stages of malaria are appealing because the parasite can be eliminated before disease onset and because they offer the unique possibility of targeting the parasite with both antibodies and T cells. Although the role of CD8+ T cells in preerythrocytic malaria stages is well documented, a highly effective T cell-inducing vaccine remains to be advanced. Here we report the development of a prime-boost immunization regimen with the Plasmodium falciparum circumsporozoite protein (PfCS) fused to the oligomer-forming vaccinia virus A27 protein and a modified vaccinia virus Ankara (MVA) vector expressing PfCS. This protocol induced polyfunctional CD8+ T cells with an effector memory phenotype and high PfCS antibody levels. These immune responses correlated with inhibition of liver-stage parasitemia in 80% and sterile protection in 40% of mice challenged with a transgenic P. berghei parasite line that expressed PfCS. Our findings underscore the potential of T and B cell immunization strategies for improving protective effectiveness against malaria.

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 Vaccinated C57BL/6 Mice Develop Protective and Memory T Cell Responses to Coccidioides posadasii Infection in the Absence of Interleukin-10

2013 ◽  
Vol 82 (2) ◽  
pp. 903-913 ◽  
Author(s):  
Chiung-Yu Hung ◽  
Natalia Castro-Lopez ◽  
Garry T. Cole
Keyword(s):  
T Cells ◽  
T Cell ◽  
Ex Vivo ◽  
Interleukin 10 ◽  
Effector Memory ◽  
Wild Type ◽  
Coccidioides Posadasii ◽  
Content Type ◽  
Cell Immunity ◽  
Ifn Γ

ABSTRACTHigh concentrations of lung tissue-associated interleukin-10 (IL-10), an anti-inflammatory and immunosuppressive cytokine, correlate with susceptibility of mice toCoccidioidesspp. infection. In this study, we found that macrophages, dendritic cells, neutrophils, and both CD8+and CD4+T cells recruited toCoccidioides posadasii-infected lungs of nonvaccinated and vaccinated mice contributed to the production of IL-10. The major IL-10-producing leukocytes were CD8+T cells, neutrophils, and macrophages in lungs of nonvaccinated mice, while both Foxp3+and Foxp3−subsets of IL-10+CD4+T cells were significantly elevated in vaccinated mice. Profiles of the recruited leukocytes in lungs revealed that only CD4+T cells were significantly increased inIL-10−/−knockout mice compared to their wild-type counterparts. Furthermore,ex vivorecall assays showed that CD4+T cells isolated from vaccinatedIL-10−/−mice compared to vaccinated wild-type mice produced significantly higher amounts of IL-2, gamma interferon (IFN-γ), IL-4, IL-6, and IL-17A in the presence of a coccidioidal antigen, indicating that IL-10 suppresses Th1, Th2, and Th17 immunity toCoccidioidesinfection. Analysis of absolute numbers of CD44+CD62L−CD4+T effector memory T cells (TEM) and IFN-γ- and IL-17A-producing CD4+T cells in the lungs ofCoccidioides-infected mice correlated with better fungal clearance in nonvaccinatedIL-10−/−mice than in nonvaccinated wild-type mice. Our results suggest that IL-10 suppresses CD4+T-cell immunity in nonvaccinated mice duringCoccidioidesinfection but does not impede the development of a memory response nor exacerbate immunopathology of vaccinated mice over at least a 4-month period after the last immunization.

scholarly journals Bridging Computational Vaccinology and Vaccine Development Through Systematic Identification, Characterization, and Downselection of Conserved and Variable Circumsporozoite Protein CD4 T Cell Epitopes From Diverse Plasmodium falciparum Strains

2021 ◽  
Vol 12 ◽  
Author(s):  
Amy R. Noe ◽  
Frances E. Terry ◽  
Brian C. Schanen ◽  
Emily Sassano ◽  
Pooja Hindocha ◽  
...  
Keyword(s):  
T Cells ◽  
Plasmodium Falciparum ◽  
T Cell ◽  
Cell Activation ◽  
Malaria Vaccine ◽  
Class Ii ◽  
Circumsporozoite Protein ◽  
Sequence Variants ◽  
Hla Dr

An effective malaria vaccine must prevent disease in a range of populations living in regions with vastly different transmission rates and protect against genetically-diverse Plasmodium falciparum (Pf) strains. The protective efficacy afforded by the currently licensed malaria vaccine, Mosquirix™, promotes strong humoral responses to Pf circumsporozoite protein (CSP) 3D7 but protection is limited in duration and by strain variation. Helper CD4 T cells are central to development of protective immune responses, playing roles in B cell activation and maturation processes, cytokine production, and stimulation of effector T cells. Therefore, we took advantage of recent in silico modeling advances to predict and analyze human leukocyte antigen (HLA)-restricted class II epitopes from PfCSP – across the entire PfCSP 3D7 sequence as well as in 539 PfCSP sequence variants – with the goal of improving PfCSP-based malaria vaccines. Specifically, we developed a systematic workflow to identify peptide sequences capable of binding HLA-DR in a context relevant to achieving broad human population coverage utilizing cognate T cell help and with limited T regulatory cell activation triggers. Through this workflow, we identified seven predicted class II epitope clusters in the N- and C-terminal regions of PfCSP 3D7 and an additional eight clusters through comparative analysis of 539 PfCSP sequence variants. A subset of these predicted class II epitope clusters was synthesized as peptides and assessed for HLA-DR binding in vitro. Further, we characterized the functional capacity of these peptides to prime and activate human peripheral blood mononuclear cells (PBMCs), by monitoring cytokine response profiles using MIMIC® technology (Modular IMmune In vitro Construct). Utilizing this decision framework, we found sufficient differential cellular activation and cytokine profiles among HLA-DR-matched PBMC donors to downselect class II epitope clusters for inclusion in a vaccine targeting PfCSP. Importantly, the downselected clusters are not highly conserved across PfCSP variants but rather, they overlap a hypervariable region (TH2R) in the C-terminus of the protein. We recommend assessing these class II epitope clusters within the context of a PfCSP vaccine, employing a test system capable of measuring immunogenicity across a broad set of HLA-DR alleles.

scholarly journals Human Memory CD4+T Cell Immune Responses against Giardia lamblia

2015 ◽  
Vol 23 (1) ◽  
pp. 11-18 ◽  
Author(s):  
Christina Skår Saghaug ◽  
Steinar Sørnes ◽  
Dimitra Peirasmaki ◽  
Staffan Svärd ◽  
Nina Langeland ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Giardia Lamblia ◽  
Mononuclear Cells ◽  
T Cell Response ◽  
Effector Memory ◽  
Content Type ◽  
Tnf Α

ABSTRACTThe intestinal protozoan parasiteGiardia lambliamay cause severe prolonged diarrheal disease or pass unnoticed as an asymptomatic infection. T cells seem to play an important role in the immune response toGiardiainfection, and memory responses may last years. Recently, TH17 responses have been found in three animal studies ofGiardiainfection. The aim of this study was to characterize the human CD4+T cell responses toGiardia. Peripheral blood mononuclear cells (PBMCs) were obtained from 21 returning travelers with recent or ongoing giardiasis and 12 low-risk healthy controls and stimulatedin vitrowithGiardia lambliaproteins. Production of tumor necrosis factor alpha (TNF-α), gamma interferon, interleukin-17A (IL-17A), IL-10, and IL-4 was measured in CD4+effector memory (EM) T cells after 24 h by flow cytometry. After 6 days of culture, activation and proliferation were measured by flow cytometry, while an array of inflammatory cytokine levels in supernatants were measured with multiplex assays. We found the number of IL-17A-producing CD4+EM T cells, as well as that of cells simultaneously producing both IL-17A and TNF-α, to be significantly elevated in theGiardia-exposed individuals after 24 h of antigen stimulation. In supernatants of PBMCs stimulated withGiardiaantigens for 6 days, we found inflammation-associated cytokines, including 1L-17A, as well as CD4+T cell activation and proliferation, to be significantly elevated in theGiardia-exposed individuals. We conclude that symptomaticGiardiainfection in humans induces a CD4+EM T cell response of which IL-17A production seems to be an important component.

scholarly journals Safety, Immunogenicity, and Efficacy of Prime-Boost Immunization with Recombinant Poxvirus FP9 and Modified Vaccinia Virus Ankara Encoding the Full-Length Plasmodium falciparum Circumsporozoite Protein

2006 ◽  
Vol 74 (5) ◽  
pp. 2706-2716 ◽  
Author(s):  
Michael Walther ◽  
Fiona M. Thompson ◽  
Susanna Dunachie ◽  
Sheila Keating ◽  
Stephen Todryk ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Immune Responses ◽  
Vaccinia Virus ◽  
Circumsporozoite Protein ◽  
Fowlpox Virus ◽  
Partial Protection ◽  
Modified Vaccinia Virus Ankara ◽  
Boost Immunization ◽  
Recombinant Fowlpox Virus ◽  
First Time

ABSTRACT Heterologous prime-boost immunization with DNA and various recombinant poxviruses encoding malaria antigens is capable of inducing strong cell-mediated immune responses and partial protection in human sporozoite challenges. Here we report a series of trials assessing recombinant fowlpox virus and modified vaccinia virus Ankara encoding the Plasmodium falciparum circumsporozoite protein in various prime-boost combinations, doses, and application routes. For the first time, these vaccines were administered intramuscularly and at doses of up to 5 × 108 PFU. Vaccines containing this antigen proved safe and induced modest immune responses but showed no evidence of efficacy in a sporozoite challenge.

scholarly journals Differentiation of Antigen-Specific T Cells with Limited Functional Capacity during Mycobacterium tuberculosis Infection

2013 ◽  
Vol 82 (1) ◽  
pp. 132-139 ◽  
Author(s):  
Yun Hee Jeong ◽  
Bo-Young Jeon ◽  
Sun-Hwa Gu ◽  
Sang-Nae Cho ◽  
Sung Jae Shin ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
T Cell ◽  
Memory T Cells ◽  
Interleukin 2 ◽  
Effector Memory ◽  
Memory Cells ◽  
Content Type ◽  
Tnf Α ◽  
Ifn Γ

ABSTRACTDespite the generation ofMycobacterium tuberculosis-specific T cell immune responses during the course of infection, only 5 to 10% of exposed individuals develop active disease, while others develop a latent infection. This phenomenon suggests defectiveM. tuberculosis-specific immunity, which necessitates more careful characterization ofM. tuberculosis-specific T cell responses. Here, we longitudinally analyzed the phenotypes and functions ofM. tuberculosis-specific T cells. In contrast to the functional exhaustion of T cells observed after chronic infection,M. tuberculosis-specific CD8+T cells differentiated into either effector (CD127loCD62Llo) or effector memory (CD127hiCD62Llo) cells, but not central memory cells (CD127hiCD62Lhi), with low programmed death 1 (PD-1) expression, even in the presence of high levels of bacteria. Additionally,M. tuberculosis-specific CD8+and CD4+T cells produced substantial levels of tumor necrosis factor alpha (TNF-α) and gamma interferon (IFN-γ), but not interleukin 2 (IL-2), uponin vitrorestimulation. AmongM. tuberculosis-specific CD8+T cells, CD127hieffector memory cells displayed slower ongoing turnover but greater survival potential. In addition, these cells produced more IFN-γ and TNF-α and displayed lytic activity upon antigen stimulation. However, the effector function ofM. tuberculosis-specific CD8+CD127hieffector memory T cells was inferior to that of canonical CD8+CD127himemory T cells generated after acute lymphocytic choriomeningitis virus infection. Collectively, our data demonstrate thatM. tuberculosis-specific T cells can differentiate into memory T cells during the course ofM. tuberculosisinfection independent of the bacterial burden but with limited functionality. These results provide a framework for further understanding the mechanisms ofM. tuberculosisinfection that can be used to develop more effective vaccines.

scholarly journals Topical CpG Adjuvantation of a Protein-Based Vaccine Induces Protective Immunity to Listeria monocytogenes

2014 ◽  
Vol 21 (3) ◽  
pp. 329-339 ◽  
Author(s):  
Wing Ki Cheng ◽  
Kathleen Wee ◽  
Tobias R. Kollmann ◽  
Jan P. Dutz
Keyword(s):  
T Cells ◽  
Listeria Monocytogenes ◽  
T Cell ◽  
Immune Responses ◽  
T Cell Responses ◽  
Parenteral Administration ◽  
Effector Memory ◽  
Dependent Manner ◽  
Content Type ◽  
Cell Responses

ABSTRACTRobust CD8+T cell responses are essential for immune protection against intracellular pathogens. Using parenteral administration of ovalbumin (OVA) protein as a model antigen, the effect of the Toll-like receptor 9 (TLR9) agonist, CpG oligodeoxynucleotide (ODN) 1826, as an adjuvant delivered either topically, subcutaneously, or intramuscularly on antigen-specific CD8+T cell responses in a mouse model was evaluated. Topical CpG adjuvant increased the frequency of OVA-specific CD8+T cells in the peripheral blood and in the spleen. The more effective strategy to administer topical CpG adjuvant to enhance CD8+T cell responses was single-dose administration at the time of antigen injection with a prime-boost regimen. Topical CpG adjuvant conferred both rapid and long-lasting protection against systemic challenge with recombinantListeria monocytogenesexpressing the cytotoxic T lymphocyte (CTL) epitope of OVA257–264(strainLm-OVA) in a TLR9-dependent manner. Topical CpG adjuvant induced a higher proportion of CD8+effector memory T cells than parenteral administration of the adjuvant. Although traditional vaccination strategies involve coformulation of antigen and adjuvant, split administration using topical adjuvant is effective and has advantages of safety and flexibility. Split administration of topical CpG ODN 1826 with parenteral protein antigen is superior to other administration strategies in enhancing both acute and memory protective CD8+T cell immune responses to subcutaneous protein vaccines. This vaccination strategy induces rapid and persistent protective immune responses against the intracellular organismL. monocytogenes.

scholarly journals IL-27 Receptor Signaling Regulates Memory CD4+T Cell Populations and Suppresses Rapid Inflammatory Responses during Secondary Malaria Infection

2013 ◽  
Vol 82 (1) ◽  
pp. 10-20 ◽  
Author(s):  
Emily Gwyer Findlay ◽  
Ana Villegas-Mendez ◽  
Noelle O'Regan ◽  
J. Brian de Souza ◽  
Lisa-Marie Grady ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Malaria Infection ◽  
Inflammatory Responses ◽  
Secondary Infection ◽  
T Cell Response ◽  
Effector Memory ◽  
Parasite Control ◽  
Content Type ◽  
Secondary Parasite

ABSTRACTInterleukin-27 (IL-27) is known to control primary CD4+T cell responses during a variety of different infections, but its role in regulating memory CD4+T responses has not been investigated in any model. In this study, we have examined the functional importance of IL-27 receptor (IL-27R) signaling in regulating the formation and maintenance of memory CD4+T cells following malaria infection and in controlling their subsequent reactivation during secondary parasite challenge. We demonstrate that although the primary effector/memory CD4+T cell response was greater in IL-27R-deficient (WSX-1−/−) mice followingPlasmodium bergheiNK65 infection than in wild-type (WT) mice, there were no significant differences in the size of the maintained memory CD4+T population(s) at 20 weeks postinfection in the spleen, liver, or bone marrow of WSX-1−/−mice compared with WT mice. However, the composition of the memory CD4+T cell pool was slightly altered in WSX-1−/−mice following clearance of primary malaria infection, with elevated numbers of late effector memory CD4+T cells in the spleen and liver and increased production of IL-2 in the spleen. Crucially, WSX-1−/−mice displayed significantly enhanced parasite control compared with WT mice following rechallenge with homologous malaria parasites. Improved parasite control in WSX-1−/−mice during secondary infection was associated with elevated systemic production of multiple inflammatory innate and adaptive cytokines and extremely rapid proliferation of antigen-experienced T cells in the liver. These data are the first to demonstrate that IL-27R signaling plays a role in regulating the magnitude and quality of secondary immune responses during rechallenge infections.

scholarly journals Mycobacterium tuberculosis Culture Filtrate Protein 10-Specific Effector/Memory CD4+and CD8+T Cells in Tubercular Pleural Fluid, with Biased Usage of T Cell Receptor Vβ Chains

2011 ◽  
Vol 79 (8) ◽  
pp. 3358-3365 ◽  
Author(s):  
Dan Qiao ◽  
Li Li ◽  
Jian Guo ◽  
Suihua Lao ◽  
Xianlan Zhang ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
T Cell ◽  
Pleural Fluid ◽  
Culture Filtrate ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Content Type ◽  
Culture Filtrate Protein

ABSTRACTT cell-mediated immunity is critical for the control ofMycobacterium tuberculosisinfection. Identifying the precise immune mechanisms that lead to control of initialM. tuberculosisinfection and preventing reactivation of latent infection are crucial for combating tuberculosis. However, a detailed understanding of the role of T cells in the immune response to infection has been hindered. In addition, there are few flow cytometry studies characterizing the Vβ repertoires of T cell receptors (TCRs) at local sites ofM. tuberculosisinfection in adult tuberculosis. In this study, we used culture filtrate protein 10 (CFP-10) fromM. tuberculosisto characterize T cells at local sites of infection. We simultaneously analyzed the correlation of the production of cytokines with TCR Vβ repertoires in CFP-10-specific CD4+and CD8+T cell subsets. For the first time, we demonstrate that CFP-10-specific CD4+or CD8+T cells from tubercular pleural fluid can produce high levels of gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α) and upregulate the expression of CD107a/b on the cell surface. The CFP-10-specific cells were effector/memory cells with a CD45RO+CD62L−CCR7−CD27−expression profile. In addition, we found CFP-10-specific CD4+and CD8+T cells in tubercular pleural fluid, with biased usage of TCR Vβ9, Vβ12, or Vβ7.2. Our findings of CFP-10-specific CD4+and CD8+T cells in tubercular pleural fluid are critical for understanding the mechanisms of the local cellular immune response and developing more effective therapeutic interventions in cases ofM. tuberculosisinfection.

scholarly journals Phosphoantigen Burst upon Plasmodium falciparum Schizont Rupture Can Distantly Activate Vγ9Vδ2 T Cells

2015 ◽  
Vol 83 (10) ◽  
pp. 3816-3824 ◽  
Author(s):  
Marianne Guenot ◽  
Séverine Loizon ◽  
Jennifer Howard ◽  
Giulia Costa ◽  
David A. Baker ◽  
...  
Keyword(s):  
T Cells ◽  
Plasmodium Falciparum ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Kinetic Studies ◽  
Blood Stage ◽  
Γδt Cells ◽  
Content Type ◽  
Vγ9vδ2 T Cells

Malaria induces potent activation and expansion of the Vγ9Vδ2 subpopulation of γδT cells, which inhibit thePlasmodium falciparumblood cycle through soluble cytotoxic mediators, abrogating merozoite invasion capacity. Intraerythrocytic stages efficiently trigger Vγ9Vδ2 T-cell activation and degranulation through poorly understood mechanisms.P. falciparumblood-stage extracts are known to contain phosphoantigens able to stimulate Vγ9Vδ2 T cells, but how these are presented by intact infected red blood cells (iRBCs) remains elusive. Here we show that, unlike activation by phosphoantigen-expressing cells, Vγ9Vδ2 T-cell activation by intact iRBCs is independent of butyrophilin expression by the iRBC, and contact with an intact iRBC is not required. Moreover, blood-stage culture supernatants proved to be as potent activators of Vγ9Vδ2 T cells as iRBCs. Bioactivity in the microenvironment is attributable to phosphoantigens, as it is dependent on the parasite DOXP pathway, on Vγ9Vδ2 TCR signaling, and on butyrophilin expression by Vγ9Vδ2 T cells. Kinetic studies showed that the phosphoantigens were released at the end of the intraerythrocytic cycle at the time of parasite egress. We document exquisite sensitivity of Vγ9Vδ2 T cells, which respond to a few thousand parasites. These data unravel a novel framework, whereby release of phosphoantigens into the extracellular milieu by sequestered parasites likely promotes activation of distant Vγ9Vδ2 T cells that in turn exert remote antiparasitic functions.

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