The role of ion channels and transporters in B cell function

项目总结/文摘

PROJECT SUMMARY/ABSTRACT B cells are a central player in the humoral immune response, which is elicited by differentiated, antibody- producing B cell-types known as plasma cells (PCs). During viral infections such as influenza or SARS-CoV2, PCs produce antibodies that neutralize viral activity. Furthermore, PCs have been implicated in the pathogenesis of many autoimmune diseases, including multiple sclerosis (MS). Thus, the capacity to modulate B cell function, notably PC differentiation and activity, has broad clinical implications. The leading therapy for specific regulation of B cell function is a monoclonal antibody targeting CD20, leading to brash depletion of virtually all B cell subsets and resulting in various side effects. Thus, there is a clinical need for molecular targets that affect B cell function in more refined and precise manners. Ion channels and transporters (ICTs) mediate the flux of ions across the lipid bilayer, which can further regulate intracellular signaling. ICTs are desirable clinical targets because 1) many are surface proteins accessible to biologics and 2) multiple small-molecule ICT modulators have already been developed. Unfortunately, though substantive evidence exists that different ICTs can contribute to different aspects of B function, this intersection remains poorly investigated. To address this gap, I will leverage transcriptomic analyses and functional genomics, coupled with experimental validations. Based on an RNA-seq and a CRISPR screen, I came across SLC4A7, a Na+/HCO3- co-transporter known to regulate intracellular pH. Deletion of SLC4A7 in B cells selectively impaired PC differentiation in vitro and in vivo. In Aim 1, I will further characterize how SLC4A7 affects PC differentiation signaling pathways, intracellular pH, and the autophagy pathway. In Aim 2, I will determine how deletion of SLC4A7 in B cells affects the immune response against influenza infection as well as the pathogenesis of a murine model for MS. Overall, this project will elucidate novel mechanisms by which intracellular pH regulates PC differentiation and reveal a novel target (SLC4A7) with which B cell function can be modulated, especially in the context of MS.