In vivo Screen Identifies Zdhhc2 as a Critical Regulator of Germinal Center B Cell Differentiation

Germinal center (GC) B cell differentiation is critical for the production of affinity-matured pathogen-specific antibodies, the dysregulation of which may lead to humoral immunodeficiency or autoimmunity. The development of an screening system for factors regulating GC B cell differentiation has been a challenge. Here we describe a small-scale screening system with NP-specific B1-8 cells and a retroviral shRNA library targeting 78 candidate genes to search for B cell-intrinsic factors that specifically regulate GC B cell differentiation. , a gene encoding palmitoyltransferase ZDHHC2 and highly expressed in GC B cells, is identified as a strong positive regulator of GC B cell differentiation. B1-8 cells transduced with -shRNA are severely compromised in differentiating into GC B cells. A further analysis of differentiated B cells transduced with -shRNA shows that is critical for the proliferation and the survival of B cells stimulated by CD40L, BAFF, and IL-21 and consequently impacts on their differentiation into GC B cells and post-GC B cells. These studies not only identify as a novel regulator of GC B cell differentiation but also represent a proof of concept of screen for regulators of GC B cell differentiation.