Regulation of late B cell differentiation by intrinsic IKKα-dependent signals

David M. Mills, Giuseppina Bonizzi, Michael Karin, Robert C. Rickert

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

NF-κB-inducing kinase (NIK)-mediated IKKα phosphorylation activates the alternative NF-κB pathway, which is characterized by nuclear translocation of p52:RelB heterodimers. This alternative pathway is initiated by a select few receptors, including LT-βR, BAFF-R, and CD40. Although NIK, IKKα, and p52 are all critical regulators of LT-βR 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-κB. Here we use mice bearing targeted mutations of the IKKα activation loop Ser 176/180 (IKKαAA) to address the B cell-intrinsic functions of NIK-IKKα signaling in vivo. We find that IKKα 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-IKKα-p52 axis is not as linear and exclusive as previous studies suggest and IKKα possesses critical NF-κB-independent functions in B cells.

Original languageEnglish
Pages (from-to)6359-6364
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number15
DOIs
Publication statusPublished - Apr 10 2007

Fingerprint

Cell Differentiation
B-Lymphocytes
Phosphotransferases
Antibody Formation
Germinal Center
Humoral Immunity
Stromal Cells
Phosphorylation
Lymphocytes
Mutation

Keywords

  • Germinal center

ASJC Scopus subject areas

  • General
  • Genetics

Cite this

Regulation of late B cell differentiation by intrinsic IKKα-dependent signals. / Mills, David M.; Bonizzi, Giuseppina; Karin, Michael; Rickert, Robert C.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 104, No. 15, 10.04.2007, p. 6359-6364.

Research output: Contribution to journalArticle

@article{3981f46389a54ef6b51cc98964ed004e,
title = "Regulation of late B cell differentiation by intrinsic IKKα-dependent signals",
abstract = "NF-κB-inducing kinase (NIK)-mediated IKKα phosphorylation activates the alternative NF-κB pathway, which is characterized by nuclear translocation of p52:RelB heterodimers. This alternative pathway is initiated by a select few receptors, including LT-βR, BAFF-R, and CD40. Although NIK, IKKα, and p52 are all critical regulators of LT-βR 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-κB. Here we use mice bearing targeted mutations of the IKKα activation loop Ser 176/180 (IKKαAA) to address the B cell-intrinsic functions of NIK-IKKα signaling in vivo. We find that IKKα 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-IKKα-p52 axis is not as linear and exclusive as previous studies suggest and IKKα possesses critical NF-κB-independent functions in B cells.",
keywords = "Germinal center",
author = "Mills, {David M.} and Giuseppina Bonizzi and Michael Karin and Rickert, {Robert C.}",
year = "2007",
month = "4",
day = "10",
doi = "10.1073/pnas.0700296104",
language = "English",
volume = "104",
pages = "6359--6364",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "15",

}

TY - JOUR

T1 - Regulation of late B cell differentiation by intrinsic IKKα-dependent signals

AU - Mills, David M.

AU - Bonizzi, Giuseppina

AU - Karin, Michael

AU - Rickert, Robert C.

PY - 2007/4/10

Y1 - 2007/4/10

N2 - NF-κB-inducing kinase (NIK)-mediated IKKα phosphorylation activates the alternative NF-κB pathway, which is characterized by nuclear translocation of p52:RelB heterodimers. This alternative pathway is initiated by a select few receptors, including LT-βR, BAFF-R, and CD40. Although NIK, IKKα, and p52 are all critical regulators of LT-βR 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-κB. Here we use mice bearing targeted mutations of the IKKα activation loop Ser 176/180 (IKKαAA) to address the B cell-intrinsic functions of NIK-IKKα signaling in vivo. We find that IKKα 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-IKKα-p52 axis is not as linear and exclusive as previous studies suggest and IKKα possesses critical NF-κB-independent functions in B cells.

AB - NF-κB-inducing kinase (NIK)-mediated IKKα phosphorylation activates the alternative NF-κB pathway, which is characterized by nuclear translocation of p52:RelB heterodimers. This alternative pathway is initiated by a select few receptors, including LT-βR, BAFF-R, and CD40. Although NIK, IKKα, and p52 are all critical regulators of LT-βR 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-κB. Here we use mice bearing targeted mutations of the IKKα activation loop Ser 176/180 (IKKαAA) to address the B cell-intrinsic functions of NIK-IKKα signaling in vivo. We find that IKKα 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-IKKα-p52 axis is not as linear and exclusive as previous studies suggest and IKKα possesses critical NF-κB-independent functions in B cells.

KW - Germinal center

UR - http://www.scopus.com/inward/record.url?scp=34547535924&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34547535924&partnerID=8YFLogxK

U2 - 10.1073/pnas.0700296104

DO - 10.1073/pnas.0700296104

M3 - Article

VL - 104

SP - 6359

EP - 6364

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 15

ER -