Neutrophils induce effective antibody responses to the pneumococcal conjugate vaccine by inhibiting T regulatory cells

Neutrophils are required for production of protective antibodies in response to the pneumococcal conjugate vaccine (PCV); however, the mechanisms behind that are not known. Using a mouse model, we found that depletion of neutrophils at the time of vaccination in female mice led to aberrant T-cell responses in the spleen, resulting in increased T regulatory cells (Tregs) that was accompanied by a dysregulated cytokine environment. We found that after vaccination, neutrophils influx into secondary lymphoid organs and increase expression of T-cell engaging or inhibiting markers. When we depleted Tregs in neutrophil-deficient mice at the time of vaccination, the opsonic activity of the antibodies and the ability of the sera to protect naïve hosts against pneumococcal infection significantly increased compared with control mice. Importantly, we examined responses after PCV administration in human female participants and found that PCV altered neutrophil phenotype. Additionally, in vitro coculture of donor neutrophils with their peripheral blood mononuclear cells at 1 wk after vaccination resulted in lower percentage and proliferation of FOXP3+ T cells, showing the clinical relevance of this phenotype. This work reveals a new mechanism by which neutrophils ensure protective Ab responses to vaccination by suppressing Tregs.