Author:
Quotti Tubi Laura,Mandato Elisa,Canovas Nunes Sara,Arjomand Arash,Zaffino Fortunato,Manni Sabrina,Casellato Alessandro,Macaccaro Paolo,Vitulo Nicola,Zumerle Sara,Filhol Odile,Boldyreff Brigitte,Siebel Christian W.,Viola Antonella,Valle Giorgio,Mainoldi Federica,Casola Stefano,Cancila Valeria,Gulino Alessandro,Tripodo Claudio,Pizzi Marco,Dei Tos Angelo Paolo,Trentin Livio,Semenzato Gianpietro,Piazza Francesco
Abstract
Serine-Threonine kinase CK2 supports malignant B-lymphocyte growth but its role in B-cell development and activation is largely unknown. Here, we describe the first B-cell specific knockout (KO) mouse model of the β regulatory subunit of CK2. CK2βKO mice present an increase in marginal zone (MZ) and a reduction in follicular B cells, suggesting a role for CK2 in the regulation of the B cell receptor (BCR) and NOTCH2 signaling pathways. Biochemical analyses demonstrate an increased activation of the NOTCH2 pathway in CK2βKO animals, which sustains MZ B-cell development. Transcriptomic analyses indicate alterations in biological processes involved in immune response and B-cell activation. Upon sheep red blood cells (SRBC) immunization CK2βKO mice exhibit enlarged germinal centers (GCs) but display a limited capacity to generate class-switched GC B cells and immunoglobulins. In vitro assays highlight that B cells lacking CK2β have an impaired signaling downstream of BCR, Toll-like receptor, CD40, and IL-4R all crucial for B-cell activation and antigen presenting efficiency. Somatic hypermutations analysis upon 4-Hydroxy-3-nitrophenylacetyl hapten conjugated to Chicken Gamma Globulin (NP-CGG) evidences a reduced NP-specific W33L mutation frequency in CK2βKO mice suggesting the importance of the β subunit in sustaining antibody affinity maturation. Lastly, since diffuse large B cell lymphoma (DLBCL) cells derive from GC or post-GC B cells and rely on CK2 for their survival, we sought to investigate the consequences of CK2 inhibition on B cell signaling in DLBCL cells. In line with the observations in our murine model, CK2 inactivation leads to signaling defects in pathways that are essential for malignant B-lymphocyte activation.
Subject
Immunology,Immunology and Allergy
Cited by
1 articles.
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