Orchestration of the antibody response by PI3K-gamma

Project Summary Over the last decade, novel inborn errors of immunity caused by mutations in phosphoinositide 3-kinase (PI3K) genes have illuminated new biology with significant relevance for basic and translational immunology. We recently reported deficiency in the PI3Kg kinase that has distinct functions relative to the related PI3Kd complex that is considered the major PI3K in lymphocytes. A key and unexpected finding from human PI3Kg deficiency was defective antibody responses, resulting in humoral immune deficits and recurrent sinopulmonary infections requiring immunoglobulin replacement therapy. These novel insights launched us toward basic science hypotheses leveraging the power of mouse models to definitively establish an essential role for PI3Kg in the IgG antibody response and generation of IgG antibody-secreting cells (ASCs). Here, we will pursue new mechanistic questions addressing impactful knowledge gaps on the molecular basis of our discovery and its therapeutic implications. We propose three aims to address our hypothesis that B cells integrate signals transduced via PI3Kg to support cell biologic changes required for differentiation into IgG ASCs. In Aim 1, we will define downstream effects of PI3Kg in orchestrating cell biologic processes in B cells to promote IgG ASC differentiation. In Aim 2, we will dissect molecular determinants upstream of PI3Kg during differentiation of ASCs from naïve or memory B cells. Finally, in Aim 3, we will test the prediction that modulation of PI3Kg activity will modulate pathological ASC responses. Together, this proposal will elucidate new and targetable pathways that regulate the antibody response in humans and mice, with important implications for responses to infection and vaccination and for therapeutic intervention in antibody-driven disease.