Regulation of late B cell differentiation by intrinsic IKKalpha-dependent signals.
NF-kappaB-inducing kinase (NIK)-mediated IKKalpha phosphorylation activates the alternative NF-kappaB pathway, which is characterized by nuclear translocation of p52:RelB heterodimers. This alternative pathway is initiated by a select few receptors, including LT-betaR, BAFF-R, and CD40. Although NIK, IKKalpha, and p52 are all critical regulators of LT-betaR signaling in stromal cells during humoral immune responses, lymphocytes require NIK, but not p52, for optimal Ig production. This disparity suggests that NIK possesses critical cell-type-specific functions that do not depend on NF-kappaB. Here we use mice bearing targeted mutations of the IKKalpha activation loop Ser(176/180) (IKKalpha(AA)) to address the B cell-intrinsic functions of NIK-IKKalpha signaling in vivo. We find that IKKalpha(AA) B cells mount normal primary antibody responses but do not enter germinal centers. This defect likely derives from ineffective early T-B cell collaboration and leads to impaired generation of humoral memory and relatively short-lived, low-affinity antibody production. Our findings contrast with those obtained by using p52(-/-) B cells, which mount normal Ig responses, and alymphoplasia (NIK mutant) B cells, which produce very little primary Ig. Thus, the NIK-IKKalpha-p52 axis is not as linear and exclusive as previous studies suggest, and IKKalpha possesses critical NF-kappaB-independent functions in B cells.
Mills
David M
DM
Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
Bonizzi
Giuseppina
G
Karin
Michael
M
Rickert
Robert C
RC
D000818:Animals; D000906:Antibodies / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D051550:I-kappa B Kinase / Q000276:immunology / Q000378:metabolism*; D007150:Immunohistochemistry; D007156:Immunologic Memory / Q000276:immunology; D051379:Mice; D008817:Mice, Mutant Strains; D017346:Protein Serine-Threonine Kinases / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D000097782:NF-kappaB-Inducing Kinase
D000906:Antibodies; D051550:I-kappa B Kinase; D017346:Protein Serine-Threonine Kinases; D000097782:NF-kappaB-Inducing Kinase