Abstract
The development of a tuberculosis (TB) vaccine that induces sterilizing immunity to Mycobacterium tuberculosis infection has been elusive. Absence of sterilizing immunity induced by TB vaccines may be due to delayed activation of mucosal dendritic cells (DCs), and subsequent delay in antigen presentation and activation of vaccine-induced CD4+ T-cell responses. Here we show that pulmonary delivery of activated M. tuberculosis antigen-primed DCs into vaccinated mice, at the time of M. tuberculosis exposure, can overcome the delay in accumulation of vaccine-induced CD4+ T-cell responses. In addition, activating endogenous host CD103+ DCs and the CD40–CD40L pathway can similarly induce rapid accumulation of vaccine-induced lung CD4+ T-cell responses and limit early M. tuberculosis growth. Thus, our study provides proof of concept that targeting mucosal DCs can accelerate vaccine-induced T-cell responses on M. tuberculosis infection, and provide insights to overcome bottlenecks in TB vaccine efficacy.
Highlights
The development of a tuberculosis (TB) vaccine that induces sterilizing immunity to Mycobacterium tuberculosis infection has been elusive
In the current study, we hypothesized that the delay in accumulation of lung vaccine-induced CD4 þ T cells in vaccinated Mycobacterium tuberculosis (Mtb)-infected hosts is due to a delay in antigen presentation by Mtb-infected antigenpresenting cells (APCs), resulting in a bottleneck and preventing sterilizing immunity to Mtb infection
Following Mtb infection, vaccine-induced CD4 þ T-cell responses are delayed in vaccinated hosts[3,6], and could be a likely reason for the failure of TB vaccines to induce sterilizing immunity
Summary
The development of a tuberculosis (TB) vaccine that induces sterilizing immunity to Mycobacterium tuberculosis infection has been elusive. In the current study, we hypothesized that the delay in accumulation of lung vaccine-induced CD4 þ T cells in vaccinated Mtb-infected hosts is due to a delay in antigen presentation by Mtb-infected APCs, resulting in a bottleneck and preventing sterilizing immunity to Mtb infection. DC transfer into vaccinated Mtb-infected hosts results in rapid activation of vaccine-induced CD4 þ T-cell responses, substantial changes in the lung micro-environment, activation of lung alveolar macrophages and early Mtb control. These protective mechanisms are dependent on CD103 þ DCs and the CD40–CD40L activation pathway, as host-directed therapeutics targeting these pathways in vaccinated. These results provide a roadmap for the type of immune responses that a sterilizing TB vaccine should induce, representing a milestone in our mechanistic understanding of TB vaccine-mediated immune responses
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