BAFF- and TACI-Dependent Processing of BAFFR by ADAM Proteases Regulates the Survival of B Cells
Cristian R. Smulski,
Patrick Kury,
Lea M. Seidel,
Hannah S. Staiger,
Anna K. Edinger,
Laure Willen,
Maximilan Seidl,
Henry Hess,
Ulrich Salzer,
Antonius G. Rolink,
Marta Rizzi,
Pascal Schneider,
Hermann Eibel
Affiliations
Cristian R. Smulski
Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg im Breisgau, Baden-Württemberg 79106, Germany; Department of Biochemistry, University of Lausanne, Lausanne, Vaud 1066, Switzerland
Patrick Kury
Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg im Breisgau, Baden-Württemberg 79106, Germany
Lea M. Seidel
Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg im Breisgau, Baden-Württemberg 79106, Germany
Hannah S. Staiger
Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg im Breisgau, Baden-Württemberg 79106, Germany
Anna K. Edinger
Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg im Breisgau, Baden-Württemberg 79106, Germany
Laure Willen
Department of Biochemistry, University of Lausanne, Lausanne, Vaud 1066, Switzerland
Maximilan Seidl
Institute of Clinical Pathology, University Medical Center Freiburg, Freiburg im Breisgau, Baden-Württemberg 79106, Germany
Henry Hess
Merck KGaA, Darmstadt, Hesse 64293, Germany
Ulrich Salzer
Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg im Breisgau, Baden-Württemberg 79106, Germany; Department of Rheumatology and Clinical Immunology, Freiburg im Breisgau, Baden-Württemberg 79106, Germany
Antonius G. Rolink
Developmental and Molecular Immunology, Department of Biomedicine, University of Basel, Basel-Stadt 4058, Switzerland
Marta Rizzi
Department of Rheumatology and Clinical Immunology, Freiburg im Breisgau, Baden-Württemberg 79106, Germany
Pascal Schneider
Department of Biochemistry, University of Lausanne, Lausanne, Vaud 1066, Switzerland; Corresponding author
Hermann Eibel
Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg im Breisgau, Baden-Württemberg 79106, Germany; Corresponding author
Summary: B cell activating factor (BAFF) provides B cells with essential survival signals. It binds to three receptors: BAFFR, TACI, and BCMA that are differentially expressed by B cell subsets. BAFFR is early expressed in circulating B cells and provides key signals for further maturation. Here, we report that highly regulated BAFFR processing events modulate BAFF responses. BAFFR processing is triggered by BAFF binding in B cells co-expressing TACI and it is executed by the metalloproteases ADAM10 and ADAM17. The degree of BAFF oligomerization, the expression of ADAM proteins in different B cell subsets, and the activation status of the cell determine the proteases involved in BAFFR processing. Inhibition of ADAM10 augments BAFF-dependent survival of primary human B cells, whereas inhibition of ADAM17 increases BAFFR expression levels on germinal center B cells. Therefore, BAFF-induced processing of BAFFR regulates BAFF-mediated B cell responses in a TACI-dependent manner. : Smulski et al. report that the B cell survival receptor BAFFR undergoes ligand-induced shedding but only in cells co-expressing a second receptor for BAFF called TACI. BAFFR shedding can be performed by ADAM10 in circulating B cells or by ADAM17 in germinal center B cells and limits BAFF-mediated survival signals. Keywords: B cell, BAFF-receptor, BAFFR, TACI, ADAM10, ADAM17, metalloprotease, processing, ectodomain shedding, germinal center, survival
