The ubiquitin ligase Itch skews light zone selection in germinal centers

Abstract

Abstract Immunoglobulin diversification occurs in peripheral lymphoid organs, after the central tolerance checkpoints during B cell development. High levels of somatic hypermutation (SHM) of Ig genes occurs in germinal center (GC) B cells, followed by selection of mutated clones. This process is essential for generation of high affinity antibody to pathogens, but can also produce autoreactive Ig receptors. Selection mechanisms that govern antigen-driven Ig diversification are still incompletely understood. The E3 ubiquitin ligase Itch prevents the emergence of autoimmune disease and autoantibodies in humans and mice, and patients lacking Itch develop debilitating, multi-faceted, potentially fatal, autoimmune disease; yet how Itch regulates GC B cell fate or function is not well understood. By studying Itch deficient mice, we have recently shown that Itch directly limits GC B cell activity to shape antibody responses. Proteomic profiling of GC B cells uncovered that Itch deficient cells exhibit high mTORC1 and Myc activity, hallmarks of positive selection. Mixed bone marrow chimeras revealed that Itch acts within B cells to limit proportions of light zone GC cells, and Itch deficient light zone GC cells were mainly in G1/G0 rather than in cell cycle. These results support a novel role for Itch in skewing selection of GC B cells to restrict LZ accumulation and shape GC-derived humoral immunity. Determining how B cells integrate cues within GCs to navigate through LZs and DZs will aid in understanding how autoreactive clones emerge from GCs in those suffering from autoimmune disease. Supported by a grant from NIH (K22AI148597)