Ablation of regulatory T cells lead to compromised quality of humoral immunity to SA14-14-2 live attenuated Japanese encephalitis vaccine

Abstract Japanese encephalitis (JE) virus is the leading cause of encephalitis in Asia and the western Pacific. Most people infected with JE do not develop symptoms or have only mild symptoms. However, few infected people develop encephalitis and about 1 in 4 cases are fatal. Currently there is no treatment for JE however the vaccines are available. One of the most widely used vaccine against JE is live attenuated SA14-14-2, which is recommended for children and adults. However, less is known about the mechanism by which the vaccine induces protective immunity. We previously found that vaccine-induced CD4+ T cells play crucial role both in protection and in the development of protective humoral immunity. Here, we attempted to understand the role of CD4+ T cell subsets, mainly regulatory T cells (Tregs), in the mechanism of protection conferred by the vaccine. To address this, we used the Treg depletion mouse model and the TCRb −/−mouse as challenge model. We observed that depletion of Tregs lead to enhancement in germinal centre (GC) reaction to vaccine. We found a significant increase in GC-Tfh cells and GC-B cells in Treg ablation condition. We also found an increase in the magnitude of antibodies in response to vaccine particularly the IgG1 isotype. However, as marked by FRNT and the challenge studies, the neutralizing potential of the antibodies was compromised in Treg depleted condition. Altogether, the data suggest that the exclusion of Tregs may enhance the cellular and humoral response, however, that will negatively impact the protective quality of humoral immunity. Overall understanding the immunological mechanism of protective immunity conferred by this vaccine will be essential key for rational design of vaccine against JE or other flaviviruses. NII