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 

TITLE=CK2β-regulated signaling controls B cell differentiation and function

JOURNAL=Frontiers in Immunology

VOLUME=13

YEAR=2023

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.959138

DOI=10.3389/fimmu.2022.959138

ISSN=1664-3224

ABSTRACT=<p>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. CK2β<sup>KO</sup> 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 CK2β<sup>KO</sup> 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 CK2β<sup>KO</sup> mice exhibit enlarged germinal centers (GCs) but display a limited capacity to generate class-switched GC B cells and immunoglobulins. <italic>In vitro</italic> 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 CK2β<sup>KO</sup> 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.</p>