Live-Attenuated Influenza Vaccine Induces Tonsillar Follicular T Helper Cell Responses That Correlate With Antibody Induction

Abstract Background Influenza remains a major threat to public health. Live-attenuated influenza vaccines (LAIV) have been shown to be effective, particularly in children. Follicular T helper (TFH) cells provide B-cell help and are crucial for generating long-term humoral immunity. However the role of TFH cells in LAIV-induced immune responses is unknown. Methods We collected tonsils, plasma, and saliva samples from children and adults receiving LAIV prior to tonsillectomy. We measured influenza-specific TFH-cell responses after LAIV by flow cytometry and immunohistochemistry. Systemic and local antibody responses were analysed by hemagglutination inhibition assay and enzyme-linked immunosorbent assay. Results We report that LAIV induced early (3–7 days post-vaccination) activation of tonsillar follicles and influenza-specific TFH-cell (CXCR5+CD57+CD4+ T cell) responses in children, and to a lesser extent in adults. Serological analyses showed that LAIV elicited rapid (day 14) and long-term (up to 1 year post-vaccination) antibody responses (hemagglutination inhibition, influenza-specific IgG) in children, but not adults. There was an inverse correlation between pre-existing influenza-specific salivary IgA concentrations and tonsillar TFH-cell responses, and a positive correlation between tonsillar TFH-cell and systemic IgG induction after LAIV. Conclusions Our data, taken together, demonstrate an important role of tonsillar TFH cells in LAIV-induced immunity in humans.

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Induction of Cross-Reactive Hemagglutination Inhibiting Antibody and Polyfunctional CD4+ T-Cell Responses by a Recombinant Matrix-M–Adjuvanted Hemagglutinin Nanoparticle Influenza Vaccine

Clinical Infectious Diseases ◽

10.1093/cid/ciaa1673 ◽

2020 ◽

Author(s):

Vivek Shinde ◽

Rongman Cai ◽

Joyce Plested ◽

Iksung Cho ◽

Jamie Fiske ◽

...

Keyword(s):

Influenza Vaccine ◽

Hemagglutination Inhibition ◽

Geometric Mean ◽

Antibody Responses ◽

High Dose ◽

Pivotal Phase ◽

Post Vaccination ◽

Treatment Groups ◽

Cell Responses ◽

Recombinant Hemagglutinin

Abstract Background Recurrent reports of suboptimal influenza vaccine effectiveness have renewed calls to develop improved, broadly cross-protective influenza vaccines. Here, we evaluated the safety and immunogenicity of a novel, saponin (Matrix-M)–adjuvanted, recombinant hemagglutinin (HA) quadrivalent nanoparticle influenza vaccine (qNIV). Methods We conducted a randomized, observer-blind, comparator-controlled (trivalent high-dose inactivated influenza vaccine [IIV3-HD] or quadrivalent recombinant influenza vaccine [RIV4]), safety and immunogenicity trial of qNIV (5 doses/formulations) in healthy adults ≥65 years. Vaccine immunogenicity was measured by hemagglutination-inhibition assays using reagents that express wild-type hemagglutination inhibition (wt-HAI) sequences and cell-mediated immune responses. Results A total of 1375 participants were randomized, immunized, and followed for safety and immunogenicity. Matrix-M–adjuvanted qNIV induced superior wt-HAI antibody responses against 5 of 6 homologous or drifted strains compared with unadjuvanted qNIV. Adjuvanted qNIV induced post-vaccination wt-HAI antibody responses at day 28 that were statistically higher than IIV3-HD against a panel of homologous or drifted A/H3N2 strains, similar to IIV3-HD against homologous A/H1N1 and B (Victoria) strains and similar to RIV4 against all homologous and drifted strains evaluated. The qNIV formulation with 75 µg Matrix-M adjuvant induced substantially higher post-vaccination geometric mean fold increases of influenza HA-specific polyfunctional CD4+ T cells compared with IIV3-HD or RIV4. Overall, similar frequencies of solicited and unsolicited adverse events were reported in all treatment groups. Conclusions qNIV with 75 µg Matrix-M adjuvant was well tolerated and induced robust antibody and cellular responses, notably against both homologous and drifted A/H3N2 viruses. Further investigation in a pivotal phase 3 trial is underway. Clinical Trials Registration NCT03658629.

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Role of IL-17 and Th17 Cells in Liver Diseases

Clinical and Developmental Immunology ◽

10.1155/2011/345803 ◽

2011 ◽

Vol 2011 ◽

pp. 1-12 ◽

Cited By ~ 137

Author(s):

Linda Hammerich ◽

Felix Heymann ◽

Frank Tacke

Keyword(s):

Chemokine Receptors ◽

Liver Diseases ◽

Th17 Cells ◽

Hepatic Inflammation ◽

T Helper ◽

Disease Etiology ◽

Cell Recruitment ◽

Cell Responses ◽

Injured Liver

Unbalanced Th1/Th2 T-cell responses in the liver are a characteristic of hepatic inflammation and subsequent liver fibrosis. The recently discovered Th17 cells, a subtype of CD4+T-helper cells mainly producing IL-17 and IL-22, have initially been linked to host defense against infections and to autoimmunity. Their preferred differentiation upon TGFβand IL-6, two cytokines abundantly present in injured liver, makes a contribution of Th17 cells to hepatic inflammation very likely. Indeed, initial studies in humans revealed activated Th17 cells and Th17-related cytokines in various liver diseases. However, functional experiments in mouse models are not fully conclusive at present, and the pathogenic contribution of Th17 cells to liver inflammation might vary upon the disease etiology, for example, between infectious and autoimmune disorders. Understanding the chemokines and chemokine receptors promoting hepatic Th17 cell recruitment (possibly CCR6 or CCR4) might reveal new therapeutic targets interfering with Th17 migration or differentiation in liver disease.

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HIV-specific T-cell Responses and Generalized Activation in HIV-1 Infected Long-term Non-progressors and Progressors from South India

Current HIV Research ◽

10.2174/1570162x17666181212122607 ◽

2019 ◽

Vol 16 (4) ◽

pp. 302-314

Author(s):

Chinnambedu Ravichandran Swathirajan ◽

Ramachandran Vignesh ◽

Greer Waldrop ◽

Uma Shanmugasundaram ◽

Pannerselvam Nandagopal ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Cd4 T Cell ◽

Cell Responses ◽

Activation Rates ◽

Hiv 1

Background:Anti-viral cytokine expressions by cytotoxic T-cells and lower activation rates have been reported to correlate with suppressed HIV replication in long-term non-progressors (LTNP). Immune mechanisms underlying disease non-progression in LTNP might vary with HIV-1 subtype and geographical locations.Objective:This study evaluates cytokine expression and T-cells activation in relation to disease non-progression in LTNP.Methods:HIV-1 Subtype C infected LTNP (n=20) and progressors (n=15) were enrolled and flowcytometry assays were performed to study HIV-specific CD8 T-cells expressing IL-2, IFN-γ, TNF-α and MIP-1β against gag and env peptides. CD4+ T-cell activation was evaluated by surface expression of HLADR and CD38.Results:Proportions of cytokines studied did not differ significantly between LTNP and progressors, while contrasting correlations with disease progression markers were observed in LTNP. CD4+ T-cell activation rates were significantly lower in LTNP compared to progressors which indicate the potential role of T-cell activation rates in disease non-progression in LTNP.Conclusion:LTNP and progressors showed similar CD8+ T-cell responses, but final conclusions can be drawn only by comparing multiple immune factors in larger LTNP cohort with HIV-1 infected individuals at various levels of disease progression. A possible role of HIV-1 subtype variation and ethnic differences in addition to host-genetic and viral factors cannot be ruled out.

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Defining and Refining Tfh Cells in Antibody Responses and The Role of OX40 Costimulation.

Transplantation Journal ◽

10.1097/00007890-201407151-00109 ◽

2014 ◽

Vol 98 ◽

pp. 34

Author(s):

P. Zhao ◽

C. Wu ◽

W. Liu ◽

X. Xiao ◽

Y. Peng ◽

...

Keyword(s):

Antibody Responses ◽

Tfh Cells

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Pathogen-Associated Molecular Patterns Induced Crosstalk between Dendritic Cells, T Helper Cells, and Natural Killer Helper Cells Can Improve Dendritic Cell Vaccination

Mediators of Inflammation ◽

10.1155/2016/5740373 ◽

2016 ◽

Vol 2016 ◽

pp. 1-12 ◽

Cited By ~ 8

Author(s):

Tammy Oth ◽

Joris Vanderlocht ◽

Catharina H. M. J. Van Elssen ◽

Gerard M. J. Bos ◽

Wilfred T. V. Germeraad

Keyword(s):

Dendritic Cells ◽

Nk Cells ◽

Natural Killer ◽

Specific Pattern ◽

Dendritic Cell Vaccination ◽

T Helper ◽

Cell Responses ◽

Helper Cells ◽

Molecular Patterns

A coordinated cellular interplay is of crucial importance in both host defense against pathogens and malignantly transformed cells. The various interactions of Dendritic Cells (DC), Natural Killer (NK) cells, and T helper (Th) cells can be influenced by a variety of pathogen-associated molecular patterns (PAMPs) and will lead to enhanced CD8+effector T cell responses. Specific Pattern Recognition Receptor (PRR) triggering during maturation enables DC to enhance Th1 as well as NK helper cell responses. This effect is correlated with the amount of IL-12p70 released by DC. Activated NK cells are able to amplify the proinflammatory cytokine profile of DC via the release of IFN-γ. The knowledge on how PAMP recognition can modulate the DC is of importance for the design and definition of appropriate therapeutic cancer vaccines. In this review we will discuss the potential role of specific PAMP-matured DC in optimizing therapeutic DC-based vaccines, as some of these DC are efficiently activating Th1, NK cells, and cytotoxic T cells. Moreover, to optimize these vaccines, also the inhibitory effects of tumor-derived suppressive factors, for example, on the NK-DC crosstalk, should be taken into account. Finally, the suppressive role of the tumor microenvironment in vaccination efficacy and some proposals to overcome this by using combination therapies will be described.

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Frontiers of Autoantibodies in Autoimmune Disorders: Crosstalk Between Tfh/Tfr and Regulatory B Cells

Frontiers in Immunology ◽

10.3389/fimmu.2021.641013 ◽

2021 ◽

Vol 12 ◽

Author(s):

Tingting Ding ◽

Rui Su ◽

Ruihe Wu ◽

Hongwei Xue ◽

Yanyan Wang ◽

...

Keyword(s):

B Cells ◽

Autoimmune Diseases ◽

Treg Cells ◽

Regulatory B Cells ◽

Cellular Mechanisms ◽

Autoantibody Production ◽

Cell Responses ◽

Tfh Cells ◽

Follicular Helper

Balance of Tfh/Tfr cell is critically important for the maintenance of immune tolerance, as evidenced by the fact that T follicular helper (Tfh) cells are central to the autoantibodies generation through providing necessary help for germinal center (GC) B cells, whereas T follicular regulatory (Tfr) cells significantly inhibit autoimmune inflammation process through restraining Tfh cell responses. However, signals underlying the regulation of Tfh and Tfr cells are largely undefined. Regulatory B cells (Bregs) is a heterogeneous subpopulation of B cells with immunosuppressive function. Considerable advances have been made in their functions to produce anti‐inflammatory cytokines and to regulate Th17, Th1, and Treg cells in autoimmune diseases. The recent identification of their correlations with dysregulated Tfr/Tfh cells and autoantibody production makes Bregs an important checkpoint in GC response. Bregs exert profound impacts on the differentiation, function, and distribution of Tfh and Tfr cells in the immune microenvironment. Thus, unraveling mechanistic information on Tfh-Breg and Tfr-Breg interactions will inspire novel implications for the establishment of homeostasis and prevention of autoantibodies in diverse diseases. This review summarizes the dysregulation of Tfh/Tfr cells in autoimmune diseases with a focus on the emerging role of Bregs in regulating the balance between Tfh and Tfr cells. The previously unsuspected crosstalk between Bregs and Tfh/Tfr cells will be beneficial to understand the cellular mechanisms of autoantibody production and evoke a revolution in immunotherapy for autoimmune diseases.

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Immune Responses Following Locoregional Treatment for Hepatocellular Carcinoma: Possible Roles of Adjuvant Immunotherapy

Pharmaceutics ◽

10.3390/pharmaceutics13091387 ◽

2021 ◽

Vol 13 (9) ◽

pp. 1387

Author(s):

Ji-Won Han ◽

Seung-Kew Yoon

Keyword(s):

Hepatocellular Carcinoma ◽

Immune Responses ◽

Immunomodulatory Effects ◽

Long Term Outcomes ◽

Locoregional Treatment ◽

Adjuvant Immunotherapy ◽

Common Cause ◽

Cell Responses

Hepatocellular carcinoma (HCC) is a common cause of cancer-related deaths worldwide. Unlike other types of cancer, HCC can be treated with locoregional treatments (LRTs) such as radiofrequency ablation (RFA) or transarterial chemoembolization (TACE). However, recurrences following LRTs are common, and strategies to improve long-term outcomes need to be developed. The exhaustion of anti-tumor immunity in HCC has been well established in many reports and the immunomodulatory effects of LRTs (enhancement of tumor antigen-specific T cell responses after RFA, reduction of effector regulatory T cells after TACE) have also been reported in several previous studies. However, a comprehensive review of previous studies and the possible roles of immunotherapy following LRTs in HCC are not known. In this review, we discuss the immunological evidence of current clinical trials using LRTs and combined immunotherapies, and the possible role of this strategy.

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Immune mechanisms: adaptive immunity

10.1093/med/9780198734444.003.0008 ◽

2016 ◽

Author(s):

Maxime Breban ◽

Hill Gaston

Keyword(s):

T Cells ◽

Animal Models ◽

Inflammatory Response ◽

Adaptive Immunity ◽

Axial Spondyloarthritis ◽

Human Peripheral Blood ◽

Antibody Responses ◽

Cell Responses ◽

B And T Lymphocytes

The role of adaptive immunity (i.e. the involvement of B and T lymphocytes) in the pathogenesis of axial spondyloarthritis has been investigated in both human disease and relevant animal models. Studies of B cell responses have not generally implicated an autoantibody in the disease, but there are abnormalities of antibody responses, particularly increased titres of antibodies to various gut bacteria. T cells are critical to the disease in animal models other than those where overexpression of a cytokine is engineered, suggesting that they are the drivers of the inflammatory response. There is convergent evidence from animal models, genetics in humans, and direct observation of human peripheral blood and joints to implicate T cells producing IL-17 under the influence of IL-23. These in turn may be responding to bacteria either in the gut or on the skin.

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Dendritic Cell Vaccination Induces HCMV Specific T-Cell Responses in Allogeneic Stem Cell Recipients.

Blood ◽

10.1182/blood.v106.11.475.475 ◽

2005 ◽

Vol 106 (11) ◽

pp. 475-475

Author(s):

Ulrich Grigoleit ◽

Markus Kapp ◽

Holger Hebart ◽

Robert Beck ◽

Gerhard Jahn ◽

...

Keyword(s):

T Cell ◽

Hcmv Infection ◽

T Cell Response ◽

Post Vaccination ◽

Cell Responses ◽

Hcmv Disease ◽

Prophylactic Vaccination ◽

Antiviral Chemotherapy ◽

Observation Period

Abstract Human cytomegalovirus (HCMV) infection remains a major and life threatening infectious complication after allogeneic stem cells transplantation (SCT). We performed a Dendritic cell (DC) vaccination trial by utilizing HCMV peptide loaded mature DC to boost HCMV specific T-cell responses which have been demonstrated to be protective against the development of HCMV disease. DCs were pulsed with nonamer peptides from the HCMV proteins pp65 and pp150, restricted by the HLA-class I elements A1,A2,A3,A11,A68 and B7. We enrolled 24 allogeneic SCT recipients, 6 patients received prophylactic vaccination in view of high risk for HCMV disease. 18 patients were vaccinated therapeutically after HCMV reactivation failed to respond to 4 weeks course of antiviral chemotherapy. Our primary objectives were safety and feasibility of DC vaccination after allogeneic SCT. As all patients with active HCMV infections already received antiviral chemotherapy at the time of DC vaccination, viral load was not a suitable efficacy parameter. Thus, evaluation of efficacy as a secondary objective was based on reconstitution of HCMV-specific CTL responses and long term control of HCMV infection. The study protocol was approved by the local ethical committee and all patients gave written informed consent. DC were generated under GMP conditions and displayed typical surface markers of mature DC (CD1a+/CD14−/CD83+). No local or systemic acute side effects occurred during the first week post vaccination. An observation period of 3 months was determined to evaluate long term side effects and control of HCMV infection. Six patients died during this observation period from other causes and one had no follow-up blood samples, so, 17 patients (5 received prophylactic and 12 received therapeutic vaccination) were evaluable. Only one patient developed Graft-Versus-Host-Disease (GVHD) grade III of the skin and gut. Due to a time lag of 2 months between vaccination and the onset of GVHD, a causative relationship seems to be unlikely. Four of the five patients receiving prophylactic vaccination never showed HCMV reactivation. 10 patients from the therapeutic group cleared their HCMV infection after a mean of 50 days post vaccination. Therefore, 15 of the 17 evaluable patients demonstrated control of HCMV infection after DC vaccination. Among these 15 patients, 10 had detectable specific T-cell response against the vaccine peptides after a mean of 23 days post vaccination. Only 2 from these 10 patients developed a further HCMV reactivation after high dose steroid therapy. Our results show that no relevant side effect was observed in this first DC vaccination trial among allogeneic SCT patients. Additionally, DC are able to induce an efficient peptide specific immune response among allogeneic SCT patients which is capable to protect against HCMV reactivation. In the future, further investigations should be performed to evaluate the feasibility of DC vaccination not only against other infectious complications but also against tumour associated antigens to induce specific T-cell response effectively targeting the particular tumour cell.

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Death Ligand Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Inhibits Experimental Autoimmune Thyroiditis

Endocrinology ◽

10.1210/en.2005-0627 ◽

2005 ◽

Vol 146 (11) ◽

pp. 4721-4726 ◽

Cited By ~ 30

Author(s):

Su He Wang ◽

Zhengyi Cao ◽

Julie M. Wolf ◽

Mary Van Antwerp ◽

James R. Baker

Keyword(s):

Autoimmune Thyroiditis ◽

T Helper ◽

Mononuclear Cell Infiltration ◽

T Helper 1 ◽

Experimental Autoimmune Thyroiditis ◽

Cell Responses ◽

Control Protein ◽

Necrosis Factor ◽

Experimental Autoimmune

The role of TNF-related apoptosis-inducing ligand (TRAIL) in autoimmune thyroiditis is unclear. We used experimental autoimmune thyroiditis to clarify the contribution of TRAIL to the development of autoimmune thyroiditis. CBA/J mice were immunized with murine thyroglobulin, and spleen cells from these mice were subsequently injected into irradiated recipient CBA/J mice. One week later, the recipient mice were treated with recombinant TRAIL or a control protein. Compared with control animals, TRAIL-treated mice developed a milder form of the disease with a significant decrease in mononuclear cell infiltration in the thyroid and less thyroid follicular destruction. Furthermore, the number of apoptotic thyrocytes and also thyroglobulin-specific T helper-1 cell responses in TRAIL-treated mice was lower than that in the control animals. This study suggests that exogenous TRAIL suppresses the development of autoimmune thyroiditis via altering the function of cells involved in the immune response. These findings may contribute toward a novel treatment autoimmune thyroiditis.

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