Bhlhe40 function in activated B and TFH cells restrains the GC reaction and prevents lymphomagenesis.
Animals
B-Lymphocytes
/ immunology
Basic Helix-Loop-Helix Transcription Factors
/ genetics
Biomarkers
Cell Differentiation
/ genetics
Disease Models, Animal
Disease Susceptibility
Gene Expression Regulation
Germinal Center
/ immunology
Homeodomain Proteins
/ genetics
Immunophenotyping
Lymphocyte Activation
/ genetics
Lymphoma, B-Cell
/ etiology
Mice
Mice, Knockout
T Follicular Helper Cells
/ immunology
Journal
The Journal of experimental medicine
ISSN: 1540-9538
Titre abrégé: J Exp Med
Pays: United States
ID NLM: 2985109R
Informations de publication
Date de publication:
07 02 2022
07 02 2022
Historique:
received:
30
06
2021
revised:
01
11
2021
accepted:
23
11
2021
entrez:
17
12
2021
pubmed:
18
12
2021
medline:
22
2
2022
Statut:
ppublish
Résumé
The generation of high-affinity antibodies against pathogens and vaccines requires the germinal center (GC) reaction, which relies on a complex interplay between specialized effector B and CD4 T lymphocytes, the GC B cells and T follicular helper (TFH) cells. Intriguingly, several positive key regulators of the GC reaction are common for both cell types. Here, we report that the transcription factor Bhlhe40 is a crucial cell-intrinsic negative regulator affecting both the B and T cell sides of the GC reaction. In activated CD4 T cells, Bhlhe40 was required to restrain proliferation, thus limiting the number of TFH cells. In B cells, Bhlhe40 executed its function in the first days after immunization by selectively restricting the generation of the earliest GC B cells but not of early memory B cells or plasmablasts. Bhlhe40-deficient mice with progressing age succumbed to a B cell lymphoma characterized by the accumulation of monoclonal GC B-like cells and polyclonal TFH cells in various tissues.
Identifiants
pubmed: 34919144
pii: 212923
doi: 10.1084/jem.20211406
pmc: PMC8689665
pii:
doi:
Substances chimiques
Basic Helix-Loop-Helix Transcription Factors
0
Bhlhe40 protein, mouse
0
Biomarkers
0
Homeodomain Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Austrian Science Fund FWF
ID : P28841
Pays : Austria
Organisme : European Research Council
Pays : International
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2021 Rauschmeier et al.
Déclaration de conflit d'intérêts
Disclosures: The authors declare no competing interests exist.
Références
Immunity. 2017 Dec 19;47(6):1142-1153.e4
pubmed: 29262350
Eur J Immunol. 2003 Feb;33(2):314-25
pubmed: 12548562
Immunity. 2008 Jun;28(6):751-62
pubmed: 18538592
Science. 2009 Aug 21;325(5943):1006-10
pubmed: 19608860
Sci Immunol. 2021 Feb 12;6(56):
pubmed: 33579751
Bioinformatics. 2015 Jan 15;31(2):166-9
pubmed: 25260700
Cancer Cell. 2005 May;7(5):445-55
pubmed: 15894265
Immunity. 2015 Dec 15;43(6):1064-74
pubmed: 26620759
Curr Top Dev Biol. 2014;110:317-38
pubmed: 25248481
Nat Protoc. 2014 Jan;9(1):171-81
pubmed: 24385147
Immunity. 2016 Sep 20;45(3):570-582
pubmed: 27566940
Nature. 2018 Aug;560(7719):494-498
pubmed: 30089906
Nat Immunol. 2017 Apr;18(4):442-455
pubmed: 28250425
Bioinformatics. 2011 Jun 15;27(12):1696-7
pubmed: 21486936
Immunity. 2015 Feb 17;42(2):239-251
pubmed: 25692700
Nucleic Acids Res. 2015 Jan;43(Database issue):D662-9
pubmed: 25352552
Eur J Immunol. 2004 May;34(5):1322-32
pubmed: 15114665
Trends Immunol. 2012 Dec;33(12):590-7
pubmed: 22920843
Science. 2009 Aug 21;325(5943):1001-5
pubmed: 19628815
Nat Protoc. 2012 Sep;7(9):1728-40
pubmed: 22936215
Cell Rep. 2020 Feb 4;30(5):1530-1541.e4
pubmed: 32023467
Nucleic Acids Res. 2018 Jul 2;46(W1):W537-W544
pubmed: 29790989
Theory Biosci. 2012 Dec;131(4):281-5
pubmed: 22872506
Nat Genet. 2008 Jan;40(1):108-12
pubmed: 18066064
J Exp Med. 1997 Aug 4;186(3):439-48
pubmed: 9236196
Genome Biol. 2014;15(12):550
pubmed: 25516281
J Exp Med. 2015 Apr 6;212(4):539-53
pubmed: 25824819
Cell. 1994 Apr 22;77(2):297-306
pubmed: 8168136
Nat Commun. 2014 Apr 03;5:3551
pubmed: 24699451
Nat Immunol. 2011 Jun;12(6):536-43
pubmed: 21572431
EMBO J. 2012 Jun 05;31(14):3130-46
pubmed: 22669466
Nat Rev Immunol. 2015 Mar;15(3):172-84
pubmed: 25712152
J Exp Med. 2018 Jul 2;215(7):1813-1821
pubmed: 29773643
J Exp Med. 2011 Aug 29;208(9):1749-56
pubmed: 21844204
Nat Immunol. 2012 Nov;13(11):1092-100
pubmed: 23001146
Cell. 2019 Feb 7;176(4):897-912.e20
pubmed: 30686579
Immunity. 2021 Sep 14;54(9):2005-2023.e10
pubmed: 34525339
J Exp Med. 2010 May 10;207(5):933-42
pubmed: 20421391
Nature. 2005 May 26;435(7041):452-8
pubmed: 15917799
Immunity. 2019 Aug 20;51(2):324-336.e5
pubmed: 31350178
Nat Immunol. 2012 Mar 11;13(4):405-11
pubmed: 22406686
BMC Genomics. 2019 Jan 18;20(1):59
pubmed: 30658577
J Exp Med. 2018 Jul 2;215(7):1823-1838
pubmed: 29773644
J Exp Med. 2017 Apr 3;214(4):1181-1198
pubmed: 28351982
Nat Immunol. 2001 Nov;2(11):1040-7
pubmed: 11668339
Immunity. 2000 Aug;13(2):199-212
pubmed: 10981963
Nat Methods. 2013 Dec;10(12):1213-8
pubmed: 24097267
Proc Natl Acad Sci U S A. 2016 Jun 14;113(24):E3394-402
pubmed: 27226296
Bioinformatics. 2009 May 1;25(9):1105-11
pubmed: 19289445
Immunity. 2016 Sep 20;45(3):471-482
pubmed: 27653600
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
Cell. 1992 Mar 6;68(5):855-67
pubmed: 1547487
Nat Rev Immunol. 2015 Mar;15(3):137-48
pubmed: 25656706
Nat Methods. 2012 Mar 04;9(4):357-9
pubmed: 22388286
Immunity. 2009 Sep 18;31(3):457-68
pubmed: 19631565
Cell. 2013 Sep 12;154(6):1370-9
pubmed: 23992847
J Clin Pathol. 2017 Mar;70(3):187-201
pubmed: 27895166
J Exp Med. 2003 May 5;197(9):1173-81
pubmed: 12732658
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
J Exp Med. 2000 Feb 7;191(3):485-94
pubmed: 10662794
Immunity. 2013 May 23;38(5):918-29
pubmed: 23684984
J Exp Med. 2011 Jun 6;208(6):1243-52
pubmed: 21576382
BMC Dev Biol. 2001;1:4
pubmed: 11299042
Immunity. 2018 Apr 17;48(4):702-715.e4
pubmed: 29669250
Science. 1997 Apr 25;276(5312):589-92
pubmed: 9110977
Cell. 2019 Jun 13;177(7):1888-1902.e21
pubmed: 31178118
Immunity. 2019 Sep 17;51(3):491-507.e7
pubmed: 31533057
Immunity. 2019 May 21;50(5):1132-1148
pubmed: 31117010
Immunology. 2014 Jan;141(1):79-95
pubmed: 24032749
Nat Rev Cancer. 2014 Aug;14(8):517-34
pubmed: 25008267
J Transl Med. 2018 Jul 17;16(1):198
pubmed: 30016977
Genome Res. 2012 Jan;22(1):134-41
pubmed: 22128135
J Exp Med. 2012 Mar 12;209(3):597-606
pubmed: 22370719
Proc Natl Acad Sci U S A. 2012 May 29;109(22):8664-9
pubmed: 22552227
Immunity. 2015 Dec 15;43(6):1075-86
pubmed: 26620760
Nat Commun. 2017 Jan 16;8:14049
pubmed: 28091601
Immunity. 2001 Nov;15(5):763-74
pubmed: 11728338
Nucleic Acids Res. 2009 Oct;37(18):e123
pubmed: 19620212
Nat Immunol. 2002 Apr;3(4):399-406
pubmed: 11896394
Nat Immunol. 2012 Nov;13(11):1083-91
pubmed: 23001145
PLoS One. 2008 Jul 23;3(7):e2762
pubmed: 18648504
Immunity. 2013 Mar 21;38(3):596-605
pubmed: 23499493
Proc Natl Acad Sci U S A. 2006 Sep 12;103(37):13789-94
pubmed: 16940357
J Immunol. 2010 Dec 15;185(12):7330-9
pubmed: 21057086
Immunol Rev. 2020 Jul;296(1):36-47
pubmed: 32557712
Nat Genet. 1997 Jun;16(2):161-70
pubmed: 9171827
J Immunol. 2014 Apr 1;192(7):3200-6
pubmed: 24591370
Nat Biotechnol. 2015 May;33(5):495-502
pubmed: 25867923