Activation and Induction of Antigen-Specific T Follicular Helper Cells Play a Critical Role in Live-Attenuated Influenza Vaccine-Induced Human Mucosal Anti-influenza Antibody Response.

Abdullah Aljurayyan,Muhammad Ahmed,Qibo Zhang,Ravi Sharma,Madhan Krishnan,Sam Leong,Stephen Gordon,Devika Rajashekar,Paul S Mcnamara,Katherine Davies,Suttida Puksuriwong,Salil Sood,Adolfo García-Sastre

doi:10.1128/jvi.00114-18

Abstract

ABSTRACTThere is increasing interest recently in developing intranasal vaccines against respiratory tract infections. The antibody response is critical for vaccine-induced protection, and T follicular helper cells (TFH) are considered important for mediating the antibody response. Most data supporting the role for TFH in the antibody response are from animal studies, and direct evidence from humans is limited, apart from the presence of TFH-like cells in blood. We studied the activation and induction of TFH and their role in the anti-influenza antibody response induced by a live-attenuated influenza vaccine (LAIV) in human nasopharynx-associated lymphoid tissue (NALT). TFH activation in adenotonsillar tissues was analyzed by flow cytometry, and anti-hemagglutinin (anti-HA) antibodies were examined following LAIV stimulation of tonsillar mononuclear cells (MNC). Induction of antigen-specific TFH by LAIV was studied by flow cytometry analysis of induced TFH and CD154 expression. LAIV induced TFH proliferation, which correlated with anti-HA antibody production, and TFH were shown to be critical for the antibody response. Induction of TFH from naive T cells by LAIV was shown in newly induced TFH expressing BCL6 and CD21, followed by the detection of anti-HA antibodies. Antigen specificity of LAIV-induced TFH was demonstrated by expression of the antigen-specific T cell activation marker CD154 upon challenge by H1N1 virus antigen or HA. LAIV-induced TFH differentiation was inhibited by BCL6, interleukin-21 (IL-21), ICOS, and CD40 signaling blocking, and that diminished anti-HA antibody production. In conclusion, we demonstrated the induction by LAIV of antigen-specific TFH in human NALT that provide critical support for the anti-influenza antibody response. Promoting antigen-specific TFH in NALT by use of intranasal vaccines may provide an effective vaccination strategy against respiratory infections in humans.IMPORTANCE Airway infections, such as influenza, are common in humans. Intranasal vaccination has been considered a biologically relevant and effective way of immunization against airway infection. The vaccine-induced antibody response is crucial for protection against infection. Recent data from animal studies suggest that one type of T cells, TFH, are important for the antibody response. However, data on whether TFH-mediated help for antibody production operates in humans are limited due to the lack of access to human immune tissue containing TFH. In this study, we demonstrate the induction of TFH in human immune tissue, providing critical support for the anti-influenza antibody response, by use of an intranasal influenza vaccine. Our findings provide direct evidence that TFH play a critical role in vaccine-induced immunity in humans and suggest a novel strategy for promoting such cells by use of intranasal vaccines against respiratory infections.

Highlights

IMPORTANCE Airway infections, such as influenza, are common in humans
Activation of T follicular helper cells (TFH) in nasopharynx-associated lymphoid tissue (NALT) was examined by live-attenuated influenza vaccine (LAIV) stimulation of adenotonsillar mononuclear cells (MNC) for 3 days, followed by enumeration of TFH numbers by use of flow cytometry
LAIV is thought to replicate in the upper respiratory tract to induce immunity through the local immune tissue NALT, and it was shown to replicate in nasal epithelial cells [25]

Summary

Introduction

IMPORTANCE Airway infections, such as influenza, are common in humans. Intranasal vaccination has been considered a biologically relevant and effective way of immunization against airway infection. Our findings provide direct evidence that TFH play a critical role in vaccineinduced immunity in humans and suggest a novel strategy for promoting such cells by use of intranasal vaccines against respiratory infections. Most of the current evidence supporting the importance of TFH in vaccination comes from animal studies, and direct evidence from humans is limited, apart from the detection of TFH-like cells, which are thought to be equivalent to TFH, in human peripheral blood samples [3, 4] Whether this TFHmediated critical help for vaccine-induced B cell antibody responses operates in humans remains largely unsubstantiated. Considering the importance of TFH for B cell antibody responses, the development of novel vaccines to induce/activate TFH may be an effective strategy for better vaccine efficacy in humans. Human adenoids and tonsils are major components of NALT and are known to be major induction sites for both mucosal and systemic immunity against upper respiratory tract pathogens, including influenza virus [10,11,12,13]

Methods

Results

Conclusion