LAG-3: a potentially important checkpoint of the humoral immune response

Abstract

Abstract Emerging infectious viruses such as Zika virus (ZIKV) pose serious threats to human health. Currently, there are no FDA-approved therapeutics or vaccines available for ZIKV. Our laboratory has developed a vaccine candidate using recombinant envelope protein (E) of the ZIKV. Our previous work has shown that neutralizing antibody responses are the protective factor upon viral challenge in BALB/c mice and non-human primates. Since lymphocyte-activation gene 3 (LAG-3) is an immune checkpoint receptor that directly interacts with MHC-II during antigen presentation, we decided to use the mouse model to investigate the effects of administering a LAG-3 blockade prior to immunization. We hypothesized that this pre-treatment may increase the number of CD4+ T helper (Th) cells available to interact with B cells in germinal centers, thus increasing the antibody response. We observed an increase in CD4+ T cells among the treatment group, changes in overall Th phenotypes, and a reduction of phenotypically exhausted CD8+ T cells. This alteration in cell populations was accompanied by an increase in vaccine potency based on ZIKV neutralizing titers. Based on preliminary observations, we believe that pre-treatment with LAG-3 blockade prior to immunization may modulate the magnitude of humoral responses by increasing Th cell activity in germinal centers. Overall, we think that LAG-3 may be an important controller of the quality of adaptive immune responses and work to further investigate these phenomena is ongoing.