Abstract The immature immune system of newborns renders poor vaccine response. However, mechanisms of limited T follicular helper (Tfh)-mediated antibody production in newborns are largely unknown. We found significantly more expression of the Tfh inhibitory genes associated with regulatory T cell (Treg) cells and IL-2 signaling in immunized newborn mice CD4+CXCR5+PD-1+Tfh cells than in adult mice. The IL-2-STAT5 signaling in CD4+CXCR5+PD-1+Foxp3+T follicular regulatory cells (Tfr) was hyperactive in newborns as compared to adults. Also, in newborns IL-6-STAT3 signaling was lower in Tfh cells but higher in Tfr cells compared to adult mice. Immunization did not elicit IL-21 expressing Tfh cells but when provided sufficient IL-21, in vitro cultured newborn T cells differentiated into Tfh-like cells. These data indicate that in newborns, dendritic cell-derived IL-6 signaling preferentially induces Treg cells to differentiate into Tfr cells, which in turn suppresses Tfh generation. Supporting this hypothesis, co-injection of newborn mice with conjugate type 14 pneumococcal polysaccharide vaccine together with IL-21 or anti-CD25 blocking antibody reduced Tfr/Tfh ratio and enhanced Tfh formation. While IL-21 elicited both IgG and IgA antibodies against vaccine, anti-CD25 antibody only improved IgA production, due in part to the elevated APRIL and TGF-β expression in T cells and fibroblast reticular cells. Since IL-21 acts both on T cells and B cells, improved IgG response in IL-21 injected mice is likely due to its direct effect on B cells. These findings highlight the differences in the programming of IL-2 and IL-6 signaling in newborn and adult Tfh cells. These differences may be exploited in devising improved vaccines for infants.