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.