In vitro differentiation of HIV-specific plasma cells for transplantable humoral immunity 3294

Description Vaccinations have reigned in numerous diseases that once plagued humanity. However, there are some pathogens, such as HIV, for which no effective vaccine exists despite considerable effort. A major goal of such vaccines is to generate sterilizing humoral immunity. While there are a variety of antibodies known to have broadly neutralizing capacity, they are difficult to induce through vaccination. We have engineered an induced pluripotent stem cell line to encode the broadly neutralizing VRC01 antibody. Using a combination of single cell RNA and ATAC sequencing of in vitro differentiating primary B cells, we have identified various transition states that these cells must pass through to become bona fide plasma cells as well as multiple bottlenecks during in vitro differentiation. This approach allowed for the dramatic improvement in plasma cell yields through properly timed STAT1 and IL-6 signaling. This differentiation scheme has been applied to stem cell-derived B cells encoding a broadly neutralizing HIV antibody to produce gp120-specific, transplantable plasma cells. We have also characterized when during in vitro differentiation plasma cell potential is present or absent starting from immature B cell stages.