IL-6 Impairs Vaccine Responses in Neonatal Mice

The inability of infants to mount proper follicular helper T (T_FH) cell response renders this age group susceptible to infectious diseases. Initial instruction of T cells by antigen presenting cells and subsequent differentiation into T_FH cells are controlled by T cell receptor signal strength, co-stimulatory molecules and cytokines such as IL-6 and IL-21. In immunized adults, IL-6 promotes T_FH development by increasing the expression of CXCR5 and the T_FH master transcription factor, B cell lymphoma 6. Underscoring the importance of IL-6 in T_FH generation, we found improved antibody responses accompanied by increased T_FH cells and decreased follicular regulatory helper T (T_FR) cells, a Foxp3 expressing inhibitory CD4⁺ T cell occupying the germinal center (GC), when a tetanus toxoid conjugated pneumococcal polysaccharide type 14 vaccine was injected in adult mice together with IL-6. Paradoxically, in neonates IL-6 containing PPS14-TT vaccine suppressed the already impaired T_FH development and antibody responses in addition to increasing T_FR cell population. Supporting the diminished T_FH development, we detected lower frequency of phospho-STAT-3⁺ T_FH in immunized neonatal T cells after IL-6 stimulation than adult cells. Moreover, IL-6 induced more phospho-STAT-3⁺ T_FR in neonatal cells than adult cells. We also measured lower expression of IL-6R on T_FH cells and higher expression on T_FR cells in neonatal cells than adult cells, a possible explanation for the difference in IL-6 induced signaling in different age groups. Supporting the flow cytometry findings, microscopic examination revealed the localization of T_reg cells in the splenic interfollicular niches of immunized adult mice compared to splenic follicles in neonatal mice. In addition to the limitations in the formation of IL-21 producing T_FH cells, neonatal mice GC B cells also expressed lower levels of IL-21R in comparison to the adult mice cells. These findings point to diminished IL-6 activity on neonatal T_FH cells as an underlying mechanism of the increased T_FR: T_FH ratio in immunized neonatal mice.