TY - JOUR
T1 - IKK-induced NF-κB1 p105 proteolysis is critical for B cell antibody responses to T cell-dependent antigen
AU - Jacque, Emilie
AU - Schweighoffer, Edina
AU - Visekruna, Alexander
AU - Papoutsopoulou, Stamatia
AU - Janzen, Julia
AU - Zillwood, Rachel
AU - Tarlinton, David M.
AU - Tybulewicz, Victor L J
AU - Ley, Steven C.
PY - 2014
Y1 - 2014
N2 - The importance of IκB kinase (IKK)-induced proteolysis of NF-κB1 p105 in B cells was investigated using Nfkb1SSAA/SSAA mice, in which this NF-κB signaling pathway is blocked. Nfkb1SSAA mutation had no effect on the development and homeostasis of follicular mature (FM) B cells. However, analysis of mixed bone marrow chimeras revealed that Nfkb1SSAA/SSAA FM B cells were completely unable to mediate T cell-dependent antibody responses. Nfkb1SSAA mutation decreased B cell antigen receptor (BCR) activation of NF-κB in FM B cells, which selectively blocked BCR stimulation of cell survival and antigen-induced differentiation into plasmablasts and germinal center B cells due to reduced expression of Bcl-2 family proteins and IRF4, respectively. In contrast, the antigen-presenting function of FM B cells and their BCR-induced migration to the follicle T cell zone border, as well as their growth and proliferation after BCR stimulation, were not affected. All of the inhibitory effects of Nfkb1SSAA mutation on B cell functions were rescued by normalizing NF-κB activation genetically. Our study identifies critical B cell-intrinsic functions for IKK-induced NF-κB1 p105 proteolysis in the antigen-induced survival and differentiation of FM B cells, which are essential for T-dependent antibody responses.
AB - The importance of IκB kinase (IKK)-induced proteolysis of NF-κB1 p105 in B cells was investigated using Nfkb1SSAA/SSAA mice, in which this NF-κB signaling pathway is blocked. Nfkb1SSAA mutation had no effect on the development and homeostasis of follicular mature (FM) B cells. However, analysis of mixed bone marrow chimeras revealed that Nfkb1SSAA/SSAA FM B cells were completely unable to mediate T cell-dependent antibody responses. Nfkb1SSAA mutation decreased B cell antigen receptor (BCR) activation of NF-κB in FM B cells, which selectively blocked BCR stimulation of cell survival and antigen-induced differentiation into plasmablasts and germinal center B cells due to reduced expression of Bcl-2 family proteins and IRF4, respectively. In contrast, the antigen-presenting function of FM B cells and their BCR-induced migration to the follicle T cell zone border, as well as their growth and proliferation after BCR stimulation, were not affected. All of the inhibitory effects of Nfkb1SSAA mutation on B cell functions were rescued by normalizing NF-κB activation genetically. Our study identifies critical B cell-intrinsic functions for IKK-induced NF-κB1 p105 proteolysis in the antigen-induced survival and differentiation of FM B cells, which are essential for T-dependent antibody responses.
UR - http://www.scopus.com/inward/record.url?scp=84907205760&partnerID=8YFLogxK
U2 - 10.1084/jem.20132019
DO - 10.1084/jem.20132019
M3 - Article
C2 - 25225457
AN - SCOPUS:84907205760
VL - 211
SP - 2085
EP - 2101
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
SN - 0022-1007
IS - 10
ER -