scholarly journals Cellular and Cytokine Responses in the Granulomas of Asymptomatic Cattle Naturally Infected with Mycobacterium bovis in Ethiopia

2020 ◽  
Vol 88 (12) ◽  
Author(s):  
Begna Tulu ◽  
Henny M. Martineau ◽  
Aboma Zewude ◽  
Fekadu Desta ◽  
David A. Jolliffe ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Bovis ◽  
Natural Infection ◽  
Stage Iv ◽  
Stage I ◽  
Content Type ◽  
Tnf Α ◽  
Ifn Γ ◽  
Culture Positive ◽  
Culture Negative

ABSTRACT Cell (CD3+ T cell and CD68+ macrophages), cytokine (interferon gamma-positive [IFN-γ+] and tumor necrosis factor alpha-positive [TNF-α+]), and effector molecule (inducible nitric oxide synthase-positive [iNOS+]) responses were evaluated in the lymph nodes and tissues of cattle naturally infected with Mycobacterium bovis. Detailed postmortem and immunohistochemical examinations of lesions were performed on 16 cows that were positive by the single intradermal cervical comparative tuberculin (SICCT) test and that were identified from dairy farms located around the city of Addis Ababa, Ethiopia. The severity of the gross lesion was significantly higher (P = 0.003) in M. bovis culture-positive cows (n = 12) than in culture-negative cows (n = 4). Immunohistochemical techniques showed that in culture-positive cows, the mean immunolabeling fraction of CD3+ T cells decreased as the stage of granuloma increased from stage I to stage IV (P < 0.001). In contrast, the CD68+ macrophage, IFN-γ+, TNF-α+, and iNOS+ immunolabeling fractions increased from stage I to stage IV (P < 0.001). In the early stages, culture-negative cows showed a significantly higher fraction of CD68+ macrophage (P = 0.03) and iNOS+ (P = 0.007) immunolabeling fractions than culture-positive cows. Similarly, at advanced granuloma stages, culture-negative cows demonstrated significantly higher mean proportions of CD3+ T cells (P < 0.001) than culture-positive cows. Thus, this study demonstrates that, following natural infection of cows with M. bovis, as the stage of granuloma increases from stage I to stage IV, the immunolabeling fraction of CD3+ cells decreases, while the CD68+ macrophage, IFN-γ+, TNF-α+, and iNOS+ immunolabeling fractions increases.

scholarly journals Cellular and Cytokine Responses in the Granulomas of Asymptomatic Cattle naturally infected with Mycobacterium bovis in Ethiopia

2020 ◽  
Author(s):  
Begna Tulu ◽  
Henny M Martineau ◽  
Aboma Zewude ◽  
Fekadu Desta ◽  
David A Jolliffe ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Bovis ◽  
Addis Ababa ◽  
Natural Infection ◽  
Stage Iv ◽  
Stage I ◽  
Tnf Α ◽  
Ifn Γ ◽  
Culture Positive ◽  
Culture Negative

ABSTRACTCellular (CD3+ T cell and CD68+ macrophages), cytokines (IFN-γ+ and TNF-α+) and effector molecule (iNOS+) responses were evaluated in the lymph nodes and tissue of cattle naturally infected with Mycobacterium bovis. Detailed post mortem and immunonohistochemical examinations of lesions were performed on 16 cows positive for single intradermal cervical comparative tuberculin test (SICCTT) and identified from dairy farms located around the Addis Ababa City. The severity of the gross lesion was significantly higher (p=0.003) in M. bovis culture positive (n=12) cows than in culture negative (n=4). Immunohistochemical techniques showed that the mean percentage labelling of CD3+ T cells decreased as the stage of granuloma increased from stage I to stage IV in culture positive cows (p<0.001). On the other hand, the proportional fraction of CD68+ macrophages and the concentrations of IFN-γ+, TNF-α+ and iNOS+ increased significantly from stage I to stage IV (p< 0.001) in culture positive cows. At the early stage of the granuloma, the culture negative cows showed significantly higher mean proportions of CD68+ macrophages (p=0.03) as well as the concentrations of iNOS+ (p=0.007) compared to culture positive cows. Similarly, at advanced granuloma stages, culture negative cows demonstrated significantly higher mean proportions of CD3+ T cells (p< 0.001) compared to culture positive cows. Thus, the present study demonstrated that following natural infection of cows with M. bovis, as the stage of granuloma increases from stage I to stage IV, the proportion of CD3+ cells decreases while the immunolabeling fraction of CD68+ macrophages, IFN-γ+, TNF-α and iNOS+ increases.

scholarly journals Elevated levels of proinflammatory and anti-inflammatory cytokines in patients with bladder cancer depending on a tumor stage

2020 ◽  
Vol 93 (1) ◽  
Author(s):  
Viktor Dmytryk ◽  
Tetiana Luhovska ◽  
Pavel Yakovlev ◽  
Olexiy Savchuk ◽  
Ludmila Ostapchenko ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Stage Iv ◽  
Tumor Stage ◽  
Stage I ◽  
Stage Ii ◽  
Stage Iii ◽  
Common Disease ◽  
Tnf Α ◽  
Ifn Γ ◽  
Th 1

Bladder Cancer (BC) is a common disease worldwide. Chronic inflammation is one of the key mechanisms for the development of BC. This study enrolled 40 patients. Preoperative plasma levels of IL-1β, IL-4, IL-6, IL-10, IL-12β, TNF-α and IFN-γ were determined by ELISA. In our study, we observed diverse changes in the levels of cytokines in patients with BC Stage I, II, III and IV. The levels of IL-1β was increased for stage I, stage II, and stage III. The level of TNF-α was increased for stage II, stage III, stage IV. The levels of IL-4, IL-6, IL-10 and IL-12β were increased in patients with stage III and IV only. The levels of IFN- γ declined for stage II, stage III and stage IV with the lowest levels in patients with Stage IV. In our study, we investigated alteration in levels of Th-1 and Th-2-like cytokine profile, but some deficiency in Th1- status discovered in patients with BC.

scholarly journals Expression of Regulatory T Cells in Jejunum, Colon, and Cervical and Mesenteric Lymph Nodes of Dogs Naturally Infected with Leishmania infantum

2014 ◽  
Vol 82 (9) ◽  
pp. 3704-3712 ◽  
Author(s):  
Maria M. Figueiredo ◽  
Beatriz Deoti ◽  
Izabela F. Amorim ◽  
Aldair J. W. Pinto ◽  
Andrea Moraes ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Lymph Nodes ◽  
Leishmania Infantum ◽  
Parasite Load ◽  
Mesenteric Lymph Nodes ◽  
Content Type ◽  
Mesenteric Lymph ◽  
Tnf Α ◽  
Ifn Γ

ABSTRACTUsing flow cytometry, we evaluated the frequencies of CD4+and CD8+T cells and Foxp3+regulatory T cells (Tregs) in mononuclear cells in the jejunum, colon, and cervical and mesenteric lymph nodes of dogs naturally infected withLeishmania infantumand in uninfected controls. All infected dogs showed chronic lymphadenitis and enteritis. Despite persistent parasite loads, no erosion or ulcers were evident in the epithelial mucosa. The colon harbored more parasites than the jejunum. Frequencies of total CD4+, total Foxp3, and CD4+Foxp3+cells were higher in the jejunum than in the colon. Despite negative enzyme-linked immunosorbent assay (ELISA) serum results for cytokines, levels of interleukin-10 (IL-10), gamma interferon (IFN-γ), transforming growth factor beta (TGF-β), and tumor necrosis factor alpha (TNF-α) were higher in the jejunum than in the colon for infected dogs. However, IL-4 levels were higher in the colon than in the jejunum for infected dogs. There was no observed correlation between clinical signs and histopathological changes or immunological and parasitological findings in the gastrointestinal tract (GIT) of canines with visceral leishmaniasis. However, distinct segments of the GIT presented different immunological and parasitological responses. The jejunum showed a lower parasite load, with increased frequencies and expression of CD4, Foxp3, and CD8 receptors and IL-10, TGF-β, IFN-γ, and TNF-α cytokines. The colon showed a higher parasite load, with increasing expression of IL-4.Leishmania infantuminfection increased expression of CD4, Foxp3, IL-10, TGF-β, IFN-γ, and TNF-α and reduced CD8 and IL-4 expression in both the jejunum and the colon.

scholarly journals Protein Energy Malnutrition during Vaccination Has Limited Influence on Vaccine Efficacy but Abolishes Immunity if Administered during Mycobacterium tuberculosis Infection

2015 ◽  
Vol 83 (5) ◽  
pp. 2118-2126 ◽  
Author(s):  
Truc Hoang ◽  
Else Marie Agger ◽  
Joseph P. Cassidy ◽  
Jan P. Christensen ◽  
Peter Andersen
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
T Cell ◽  
Cd4 T Cells ◽  
Protein Energy Malnutrition ◽  
T Cell Subsets ◽  
Content Type ◽  
Protein Energy ◽  
Tnf Α ◽  
Ifn Γ

Protein energy malnutrition (PEM) increases susceptibility to infectious diseases, including tuberculosis (TB), but it is not clear how PEM influences vaccine-promoted immunity to TB. We demonstrate that PEM during low-level steady-state TB infection in a mouse model results in rapid relapse ofMycobacterium tuberculosis, as well as increased pathology, in bothMycobacterium bovisBCG-vaccinated and unvaccinated animals. PEM did not change the overall numbers of CD4 T cells in BCG-vaccinated animals but resulted in an almost complete loss of antigen-specific cytokine production. Furthermore, there was a change in cytokine expression characterized by a gradual loss of multifunctional antigen-specific CD4 T cells and an increased proportion of effector cells expressing gamma interferon and tumor necrosis factor alpha (IFN-γ+TNF-α+and IFN-γ+cells). PEM duringM. tuberculosisinfection completely blocked the protection afforded by the H56-CAF01 subunit vaccine, and this was associated with a very substantial loss of the interleukin-2-positive memory CD4 T cells promoted by this vaccine. Similarly, PEM during the vaccination phase markedly reduced the H56-CAF01 vaccine response, influencing all cytokine-producing CD4 T cell subsets, with the exception of CD4 T cells positive for TNF-α only. Importantly, this impairment was reversible and resupplementation of protein during infection rescued both the vaccine-promoted T cell response and the protective effect of the vaccine againstM. tuberculosisinfection.

scholarly journals Listeria-Vectored Vaccine Expressing the Mycobacterium tuberculosis 30-Kilodalton Major Secretory Protein via the Constitutively Active prfA* Regulon Boosts Mycobacterium bovis BCG Efficacy against Tuberculosis

2017 ◽  
Vol 85 (9) ◽  
Author(s):  
Qingmei Jia ◽  
Barbara Jane Dillon ◽  
Saša Masleša-Galić ◽  
Marcus A. Horwitz
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
Mycobacterium Bovis ◽  
Interleukin 2 ◽  
Secretory Protein ◽  
Broth Culture ◽  
Listeriolysin O ◽  
Content Type ◽  
Ifn Γ ◽  
Constitutively Active

ABSTRACT A potent vaccine against tuberculosis, one of the world's deadliest diseases, is needed to enhance the immunity of people worldwide, most of whom have been vaccinated with the partially effective Mycobacterium bovis BCG vaccine. Here we investigate novel live attenuated recombinant Listeria monocytogenes (rLm) vaccines expressing the Mycobacterium tuberculosis 30-kDa major secretory protein (r30/antigen 85B [Ag85B]) (rLm30) as heterologous booster vaccines in animals primed with BCG. Using three attenuated L. monocytogenes vectors, L. monocytogenes ΔactA (LmI), L. monocytogenes ΔactA ΔinlB (LmII), and L. monocytogenes ΔactA ΔinlB prfA* (LmIII), we constructed five rLm30 vaccine candidates expressing r30 linked in frame to the L. monocytogenes listeriolysin O signal sequence and driven by the hly promoter (h30) or linked in frame to the ActA N-terminal 100 amino acids and driven by the actA promoter (a30). All five rLm30 vaccines secreted r30 in broth and macrophages; while rLm30 expressing r30 via a constitutively active prfA* regulon (rLmIII/a30) expressed the largest amount of r30 in broth culture, all five rLm30 vaccines expressed equivalent amounts of r30 in infected macrophages. In comparative studies, boosting of BCG-immunized mice with rLmIII/a30 induced the strongest antigen-specific T-cell responses, including splenic and lung polyfunctional CD4+ T cells expressing the three cytokines interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), and interleukin-2 (IL-2) (P < 0.001) and splenic and lung CD8+ T cells expressing IFN-γ (P < 0.0001). In mice and guinea pigs, the rLmIII/a30 and rLmI/h30 vaccines were generally more potent booster vaccines than r30 with an adjuvant and a recombinant adenovirus vaccine expressing r30. In a setting in which BCG alone was highly immunoprotective, boosting of mice with rLmIII/a30, the most potent of the vaccines, significantly enhanced protection against aerosolized M. tuberculosis (P < 0.01).

scholarly journals Effector CD8+T Cells Are Generated in Response to an Immunodominant Epitope in Type III Effector YopE during Primary Yersinia pseudotuberculosis Infection

2014 ◽  
Vol 82 (7) ◽  
pp. 3033-3044 ◽  
Author(s):  
Yue Zhang ◽  
Patricio Mena ◽  
Galina Romanov ◽  
James B. Bliska
Keyword(s):  
T Cells ◽  
Primary Infection ◽  
Yersinia Pseudotuberculosis ◽  
Intracellular Cytokine Staining ◽  
Host Cells ◽  
Membrane Localization ◽  
Content Type ◽  
Terminal Domain ◽  
Tnf Α ◽  
Ifn Γ

ABSTRACTYopE is a virulence factor that is secreted into host cells infected byYersiniaspecies. The YopE C-terminal domain has GTPase-activating protein (GAP) activity. The YopE N-terminal domain contains an epitope that is an immunodominant CD8+T cell antigen during primary infection of C57BL/6 mice withYersinia pseudotuberculosis. The characteristics of the CD8+T cells generated in response to the epitope, which comprises YopE amino acid residues 69 to 77 (YopE69–77), and the features of YopE that are important for antigenicity during primary infection, are unknown. Following intravenous infection of naïve C57BL/6 mice with ayopEGAP mutant (the R144A mutant), flow cytometry analysis of splenocytes by tetramer and intracellular cytokine staining over a time course showed that YopE69–77-specific CD8+T cells producing gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α) were generated by day 7, with a peak at day 14. In addition, ∼80% of YopE69–77-specific CD8+T cells were positive for KLRG1, a memory phenotype marker, at day 21. To determine if residues that regulate YopE activity by ubiquitination or membrane localization affect the antigenicity of YopE69–77, mice were infected with ayopEubiquitination or membrane localization mutant (the R62K or L55N I59N L63N mutant, respectively). These mutants elicited YopE69–77-specific CD8+T cells producing IFN-γ and TNF-α with kinetics and magnitudes similar to those of the parental R144A strain, indicating that primary infection primes effector CD8+T cells independently of the ubiquitination or membrane localization of YopE. Additionally, at day 7, there was an unexpected positive correlation between the numbers of YopE69–77-specific CD8+T cells and CD11b+cells, but not between the numbers of YopE69–77-specific CD8+T cells and bacterial cells, in spleens, suggesting that the innate immune response contributes to the immunodominance of YopE69–77.

scholarly journals Mycobacterium bovis BCG Vaccination Induces Divergent Proinflammatory or Regulatory T Cell Responses in Adults

2015 ◽  
Vol 22 (7) ◽  
pp. 778-788 ◽  
Author(s):  
Mardi C. Boer ◽  
Corine Prins ◽  
Krista E. van Meijgaarden ◽  
Jaap T. van Dissel ◽  
Tom H. M. Ottenhoff ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mycobacterium Bovis ◽  
Regulatory T Cell ◽  
Cell Response ◽  
T Cell Response ◽  
Bcg Vaccination ◽  
Cell Responses ◽  
Tnf Α ◽  
Ifn Γ

ABSTRACTMycobacterium bovisbacillus Calmette-Guérin (BCG), the only currently available vaccine against tuberculosis, induces variable protection in adults. Immune correlates of protection are lacking, and analyses on cytokine-producing T cell subsets in protected versus unprotected cohorts have yielded inconsistent results. We studied the primary T cell response, both proinflammatory and regulatory T cell responses, induced by BCG vaccination in adults. Twelve healthy adult volunteers who were tuberculin skin test (TST) negative, QuantiFERON test (QFT) negative, and BCG naive were vaccinated with BCG and followed up prospectively. BCG vaccination induced an unexpectedly dichotomous immune response in this small, BCG-naive, young-adult cohort: BCG vaccination induced either gamma interferon-positive (IFN-γ+) interleukin 2-positive (IL-2+) tumor necrosis factor α-positive (TNF-α+) polyfunctional CD4+T cells concurrent with CD4+IL-17A+and CD8+IFN-γ+T cells or, in contrast, virtually absent cytokine responses with induction of CD8+regulatory T cells. Significant induction of polyfunctional CD4+IFN-γ+IL-2+TNF-α+T cells and IFN-γ production by peripheral blood mononuclear cells (PBMCs) was confined to individuals with strong immunization-induced local skin inflammation and increased serum C-reactive protein (CRP). Conversely, in individuals with mild inflammation, regulatory-like CD8+T cells were uniquely induced. Thus, BCG vaccination either induced a broad proinflammatory T cell response with local inflammatory reactogenicity or, in contrast, a predominant CD8+regulatory T cell response with mild local inflammation, poor cytokine induction, and absent polyfunctional CD4+T cells. Further detailed fine mapping of the heterogeneous host response to BCG vaccination using classical and nonclassical immune markers will enhance our understanding of the mechanisms and determinants that underlie the induction of apparently opposite immune responses and how these impact the ability of BCG to induce protective immunity to TB.

scholarly journals Induction of Unconventional T Cells by a Mutant Mycobacterium bovis BCG Strain Formulated in Cationic Liposomes Correlates with Protection against Mycobacterium tuberculosis Infections of Immunocompromised Mice

2016 ◽  
Vol 23 (7) ◽  
pp. 638-647 ◽  
Author(s):  
Steven C. Derrick ◽  
Idalia Yabe ◽  
Sheldon Morris ◽  
Siobhan Cowley
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mycobacterium Bovis ◽  
Ammonium Bromide ◽  
Control Groups ◽  
Content Type ◽  
Ifn Γ ◽  
Immunocompromised Mice ◽  
Mycobacterial Growth

Earlier studies aimed at defining protective immunity induced byMycobacterium bovisBCG immunization have largely focused on the induction of antituberculosis CD4+and CD8+T cell responses. Here we describe a vaccine consisting of a BCGΔmmaA4deletion mutant formulated in dimethyl dioctadecyl-ammonium bromide (DDA) withd-(+)-trehalose 6,6′-dibehenate (TDB) (DDA/TDB) adjuvant (A4/Adj) that protected TCRδ−/−mice depleted of CD4+, CD8+, and NK1.1+T cells against an aerosol challenge withM. tuberculosis. These mice were significantly protected relative to mice immunized with a nonadjuvanted BCGΔmmaA4(BCG-A4) mutant and nonvaccinated controls at 2 months and 9 months postvaccination. In the absence of all T cells following treatment with anti-Thy1.2 antibody, the immunized mice lost the ability to control the infection. These results indicate that an unconventional T cell population was mediating protection in the absence of CD4+, CD8+, NK1.1+, and TCRγδ T cells and could exhibit memory. Focusing on CD4−CD8−double-negative (DN) T cells, we found that these cells accumulated in the lungs postchallenge significantly more in A4/Adj-immunized mice and induced significantly greater frequencies of pulmonary gamma interferon (IFN-γ)-producing cells than were seen in the nonvaccinated or nonadjuvanted BCG control groups. Moreover, pulmonary DN T cells from the A4/Adj group exhibited significantly higher IFN-γ integrated median fluorescence intensity (iMFI) values than were seen in the control groups. We also showed that enriched DN T cells from mice immunized with A4/Adj could control mycobacterial growthin vitrosignificantly better than naive whole-spleen cells. These results suggest that formulating BCG in DDA/TDB adjuvant confers superior protection in immunocompromised mice and likely involves the induction of long-lived memory DN T cells.

scholarly journals Complex T Cell Interactions Contribute to Helicobacter pylori Gastritis in Mice

2012 ◽  
Vol 81 (3) ◽  
pp. 740-752 ◽  
Author(s):  
Brian M. Gray ◽  
Clinton A. Fontaine ◽  
Sara A. Poe ◽  
Kathryn A. Eaton
Keyword(s):  
T Cells ◽  
Helicobacter Pylori ◽  
T Cell ◽  
Published Data ◽  
Proinflammatory Response ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Tnf Α ◽  
Ifn Γ ◽  
H Pylori

ABSTRACTDisease due to the gastric pathogenHelicobacter pylorivaries in severity from asymptomatic to peptic ulcer disease and cancer. Accumulating evidence suggests that one source of this variation is an abnormal host response. The goal of this study was to use a mouse model ofH. pylorigastritis to investigate the roles of regulatory T cells (Treg) as well as proinflammatory T cells (Th1 and Th17) in gastritis, gastric T cell engraftment, and gastric cytokine production. Our results support published data indicating that severe gastritis in T cell recipient mice is due to failure of Treg engraftment, that Treg ameliorate gastritis, and that the proinflammatory response is attributable to interactions between several cell subsets and cytokines. We confirmed that gamma interferon (IFN-γ) is essential for induction of gastritis but showed that IFN-γ-producing CD4 T cells are not necessary. Interleukin 17A (IL-17A) also contributed to gastritis, but to a lesser extent than IFN-γ. Tumor necrosis factor alpha (TNF-α) and IL-17F were also elevated in association with disease. These results indicate that whileH. pylori-specific CD4+T cells and IFN-γ are both essential for induction of gastritis due toH. pylori, IFN-γ production by T cells is not essential. It is likely that other proinflammatory cytokines, such as IL-17F and TNF-α, shown to be elevated in this model, also contribute to the induction of disease. We suggest that gastritis due toH. pyloriis associated with loss of immunoregulation and alteration of several cytokines and cell subsets and cannot be attributed to a single immune pathway.

scholarly journals Antibody-Dependent, Gamma Interferon-Independent Sterilizing Immunity Induced by a Subunit Malaria Vaccine

2019 ◽  
Vol 87 (10) ◽  
Author(s):  
Bhavna Chawla ◽  
Babita Mahajan ◽  
Miranda Oakley ◽  
Victoria F. Majam ◽  
Arnel Belmonte ◽  
...  
Keyword(s):  
T Cells ◽  
Protective Immunity ◽  
Malaria Vaccine ◽  
Plasmodium Yoelii ◽  
Gamma Interferon ◽  
Content Type ◽  
Malaria Vaccines ◽  
Tnf Α ◽  
Ifn Γ ◽  
Sterilizing Immunity

ABSTRACT The development of effective malaria vaccines is hampered by incomplete understanding of the immunological correlates of protective immunity. Recently, the moderate clinical efficacy of the Plasmodium falciparum circumsporozoite protein (CSP)-based RTS,S/AS01E vaccine in phase 3 studies highlighted the urgency to design and test more efficacious next-generation malaria vaccines. In this study, we report that immunization with recombinant CSP from Plasmodium yoelii (rPyCSP), when delivered in Montanide ISA 51, induced sterilizing immunity against sporozoite challenge in C57BL/6 and BALB/c strains of mice. This immunity was antibody dependent, as evidenced by the complete loss of immunity in B-cell-knockout (KO) mice and by the ability of immune sera to neutralize sporozoite infectivity in mice. Th2-type isotype IgG1 antibody levels were associated with protective immunity. The fact that immunized gamma interferon (IFN-γ)-KO mice and wild-type (WT) mice have similar levels of protective immunity and the absence of IFN-γ-producing CD4+ and CD8+ T cells in protected mice, as shown by flow cytometry, indicate that the immunity is IFN-γ independent. Protection against sporozoite challenge correlated with higher frequencies of CD4+ T cells that express interleukin-2 (IL-2), IL-4, and tumor necrosis factor alpha (TNF-α). In the RTS,S study, clinical immunity was associated with higher IgG levels and frequencies of IL-2- and TNF-α-producing CD4+ T cells. The other hallmarks of immunity in our study included an increased number of follicular B cells but a loss in follicular T helper cells. These results provide an excellent model system to evaluate the efficacy of novel adjuvants and vaccine dosage and determine the correlates of immunity in the search for superior malaria vaccine candidates.

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