There 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 (T_FH) are considered important for mediating the antibody response. Most data supporting the role for T_FH in the antibody response are from animal studies, and direct evidence from humans is limited, apart from the presence of T_FH-like cells in blood. We studied the activation and induction of T_FH and their role in the anti-influenza antibody response induced by a live-attenuated influenza vaccine (LAIV) in human nasopharynx-associated lymphoid tissue (NALT). T_FH 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 T_FH by LAIV was studied by flow cytometry analysis of induced T_FH and CD154 expression. LAIV induced T_FH proliferation, which correlated with anti-HA antibody production, and T_FH were shown to be critical for the antibody response. Induction of T_FH from naive T cells by LAIV was shown in newly induced T_FH expressing BCL6 and CD21, followed by the detection of anti-HA antibodies. Antigen specificity of LAIV-induced T_FH was demonstrated by expression of the antigen-specific T cell activation marker CD154 upon challenge by H1N1 virus antigen or HA. LAIV-induced T_FH 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 T_FH in human NALT that provide critical support for the anti-influenza antibody response. Promoting antigen-specific T_FH 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, T_FH, are important for the antibody response. However, data on whether T_FH-mediated help for antibody production operates in humans are limited due to the lack of access to human immune tissue containing T_FH In this study, we demonstrate the induction of T_FH 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 T_FH 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.

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