Receptor interacting protein kinase 1 (RIPK1) pathways regulate innate B cell developmental checkpoints and delay effector function

Abstract Mutations in RIP kinases underlie the recently described human autoimmune syndrome, CRIA, characterized by lymphadenopathy, splenomegaly, and autoantibody production. While disease mechanisms for CRIA remain undescribed, RIP kinases work together with Caspase-8 to regulate cell death, which is critical for normal differentiation of many cell types. Here, we describe a key role for RIPK1 in facilitating innate B cell differentiation and subsequent activation. By comparing RIPK1, RIPK3, and Caspase8 triple deficient and RIPK3, Caspase 8 double deficient mice, we identified selective contributions of RIPK1 to an accumulation of murine splenic Marginal Zone (MZ) B cells and B1-b cells. We used mixed bone-marrow chimeras to determine that innate B cell commitment required B cell-intrinsic RIPK1, RIPK3, and Casp8 sufficiency. RIPK1 regulated MZ B cell differentiation rather than development and RIPK1 mediates its innate immune effects independent of the RIPK1 kinase domain. NP-KLH/alum and NP-Ficoll vaccination of RIPK3, Casp8, and RIPK1 triple deficient mice revealed uniquely delayed T-dependent and T-independent IgG responses, abnormal splenic germinal center architecture, and reduced extrafollicular plasmablast formation compared to double deficient and WT mice. RIPK1 deficiency was beneficial for survival following lethal, systemic Streptococcus pneumoniae infection, confirming the functionality of innate B cell populations which increased in the absence of RIPK1. Thus, RIPK1 orchestrates B cell fate, and delayed effector function, through a B cell-intrinsic mechanism.