Grant: Project Grant

Cell surface receptors function as sensors that receive signals from the environment and transmit these signals to allow for appropriate cellular responses. These responses range from cell activation or inhibition to proliferation, differentiation and cell death. The cell surface receptor composition reflects the biological and functional requirements of various cell lineages of the immune system and aberrant receptor expression can interfere with a correctly functioning immune system. Additionally, cell surface receptors can be modified by various protein modifications that alter their functional characteristics. We identified one such protein modification - tyrosine sulfation - that is of particular relevance to human memory B cells and plasma cells using the variable lymphocyte receptor (VLR) antibody system of the evolutionarily distant sea lamprey as novel biomedical research reagent. The radically different protein architecture and the unique origins of VLR antibodies allow these reagents to bind to targets, which cannot be readily recognized by conventional antibodies. In our research proposal, we aim to (i) investigate tyrosine sulfation as novel regulatory mechanism controlling human memory B cells and plasma cells and to (ii) explore memory B cell and plasma cell specific cell surface structures identified using monoclonal VLR antibodies, determine the molecular identity of these structures and define their functional properties. The proposed study is a structure-based approach to identify and functionally characterize unique epitopes on B cells, particularly those generated by modified cell surface proteins. The distinct binding characteristics with which VLR antibodies recognize their targets will establish a new line of investigation in addressing B cell function in health and disease.