In the present work, we show that administration of either TTB NPs lacking the V2 epitope or empty NPs abrogate the efficacy of systemic vaccination by recruiting more mucosal plasmacytoid dendritic cells, reducing mucosal NKp44+ ILCs associated with decreased risk of infection, and by increasing the frequency of mucosal Ki67+CD4+ T cells and IFN-γ+NKp44-NKG2A- ILCs that correlate with increased susceptibility to infection. Here, IFNG is linked to infection.