TY - JOUR
T1 - Pax5 regulates B cell immunity by promoting PI3K signaling via PTEN down-regulation
AU - Calderón, Lesly
AU - Schindler, Karina
AU - Malin, Stephen G.
AU - Schebesta, Alexandra
AU - Sun, Qiong
AU - Schwickert, Tanja
AU - Alberti, Chiara
AU - Fischer, Maria
AU - Jaritz, Markus
AU - Tagoh, Hiromi
AU - Ebert, Anja
AU - Minnich, Martina
AU - Liston, Adrian
AU - Cochella, Luisa
AU - Busslinger, Meinrad
N1 - Publisher Copyright:
Copyright © 2021 The Authors, some rights reserved;
PY - 2021/7
Y1 - 2021/7
N2 - The transcription factor Pax5 controls B cell development, but its role in mature B cells is largely enigmatic. Here, we demonstrated that the loss of Pax5 by conditional mutagenesis in peripheral B lymphocytes led to the strong reduction of B-1a, marginal zone (MZ), and germinal center (GC) B cells as well as plasma cells. Follicular (FO) B cells tolerated the loss of Pax5 but had a shortened half-life. The Pax5-deficient FO B cells failed to proliferate upon B cell receptor or Toll-like receptor stimulation due to impaired PI3K-AKT signaling, which was caused by increased expression of PTEN, a negative regulator of the PI3K pathway. Pax5 restrained PTEN protein expression at the posttranscriptional level, likely involving Pten-targeting microRNAs. Additional PTEN loss in Pten,Pax5 double-mutant mice rescued FO B cell numbers and the development of MZ B cells but did not restore GC B cell formation. Hence, the posttranscriptional down-regulation of PTEN expression is an important function of Pax5 that facilitates the differentiation and survival of mature B cells, thereby promoting humoral immunity.
AB - The transcription factor Pax5 controls B cell development, but its role in mature B cells is largely enigmatic. Here, we demonstrated that the loss of Pax5 by conditional mutagenesis in peripheral B lymphocytes led to the strong reduction of B-1a, marginal zone (MZ), and germinal center (GC) B cells as well as plasma cells. Follicular (FO) B cells tolerated the loss of Pax5 but had a shortened half-life. The Pax5-deficient FO B cells failed to proliferate upon B cell receptor or Toll-like receptor stimulation due to impaired PI3K-AKT signaling, which was caused by increased expression of PTEN, a negative regulator of the PI3K pathway. Pax5 restrained PTEN protein expression at the posttranscriptional level, likely involving Pten-targeting microRNAs. Additional PTEN loss in Pten,Pax5 double-mutant mice rescued FO B cell numbers and the development of MZ B cells but did not restore GC B cell formation. Hence, the posttranscriptional down-regulation of PTEN expression is an important function of Pax5 that facilitates the differentiation and survival of mature B cells, thereby promoting humoral immunity.
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U2 - 10.1126/sciimmunol.abg5003
DO - 10.1126/sciimmunol.abg5003
M3 - Article
C2 - 34301800
AN - SCOPUS:85111300664
SN - 2470-9468
VL - 6
JO - Science Immunology
JF - Science Immunology
IS - 61
M1 - eabg5003
ER -