Abstract
Although anticapsular antibodies confer serotype-specific immunity to pneumococci, children increase their ability to clear colonization before these antibodies appear, suggesting involvement of other mechanisms. We previously reported that intranasal immunization of mice with pneumococci confers CD4+ T cell–dependent, antibody- and serotype-independent protection against colonization. Here we show that this immunity, rather than preventing initiation of carriage, accelerates clearance over several days, accompanied by neutrophilic infiltration of the nasopharyngeal mucosa. Adoptive transfer of immune CD4+ T cells was sufficient to confer immunity to naïve RAG1−/− mice. A critical role of interleukin (IL)-17A was demonstrated: mice lacking interferon-γ or IL-4 were protected, but not mice lacking IL-17A receptor or mice with neutrophil depletion. In vitro expression of IL-17A in response to pneumococci was assayed: lymphoid tissue from vaccinated mice expressed significantly more IL-17A than controls, and IL-17A expression from peripheral blood samples from immunized mice predicted protection in vivo. IL-17A was elicited by pneumococcal stimulation of tonsillar cells of children or adult blood but not cord blood. IL-17A increased pneumococcal killing by human neutrophils both in the absence and in the presence of antibodies and complement. We conclude that IL-17A mediates pneumococcal immunity in mice and probably in humans; its elicitation in vitro could help in the development of candidate pneumococcal vaccines.
Highlights
Streptococcus pneumoniae is an ‘‘extracellular’’ pathogen, generally considered to be killed by phagocytic ingestion, which is facilitated by opsonic antibodies
Adoptive transfer showed that CD4+ T cells are necessary and sufficient for the accelerated clearance induced by WCV: unimmunized Rag12/2 mice were infused with CD4+ T cells from mice immunized with WCV or cholera toxin (CT) alone
Splenocytes from mice immunized with WCV expressed significantly more IL-17A in response to whole cell antigen (WCA) in vitro than cells from CT control animals (Figure 2B)
Summary
Streptococcus pneumoniae (pneumococcus) is an ‘‘extracellular’’ pathogen, generally considered to be killed by phagocytic ingestion, which is facilitated by opsonic antibodies. The success of antipneumococcal serum therapy using passive transfer of serotypespecific antibodies [1] and of vaccinations based on purified or conjugated capsular antigens [2,3] clearly shows that anticapsular antibodies protect humans against pneumococcal colonization and disease. The reduction in pneumococcal disease incidence after the first year of life occurs simultaneously for both rare and common serotypes, suggesting the acquisition of one rather than many individual immune responses [6]. Since experience with conjugate vaccines has suggested that anticapsular antibodies reduce incidence of carriage but leave duration unaffected [8], this observation suggests a mechanism of acquired immunity other than anticapsular antibodies. The declines in carriage duration and invasive disease incidence precede by several years the detection of naturally-acquired anticapsular antibody in most children [6,7]. Pneumococci express non-capsular antigens common among serotypes, and certain of these have been found to Author Summary
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