The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment.
Follicular helper T (Tfh) cells provide selection signals to germinal center B cells, which is essential for long-lived antibody responses. High CXCR5 and low CCR7 expression facilitates their homing to B cell follicles and distinguishes them from T helper 1 (Th1), Th2, and Th17 cells. Here, we showed that Bcl-6 directs Tfh cell differentiation: Bcl-6-deficient T cells failed to develop into Tfh cells and could not sustain germinal center responses, whereas forced expression of Bcl-6 in CD4(+) T cells promoted expression of the hallmark Tfh cell molecules CXCR5, CXCR4, and PD-1. Bcl-6 bound to the promoters of the Th1 and Th17 cell transcriptional regulators T-bet and RORgammat and repressed IFN-gamma and IL-17 production. Bcl-6 also repressed expression of many microRNAs (miRNAs) predicted to control the Tfh cell signature, including miR-17-92, which repressed CXCR5 expression. Thus, Bcl-6 positively directs Tfh cell differentiation, through combined repression of miRNAs and transcription factors.
Yu
Di
D
Immunology and inflammation, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
Rao
Sudha
S
Tsai
Louis M
LM
Lee
Sau K
SK
He
Yiqing
Y
Sutcliffe
Elissa L
EL
Srivastava
Monika
M
Linterman
Michelle
M
Zheng
Lei
L
Simpson
Nicholas
N
Ellyard
Julia I
JI
Parish
Ian A
IA
Ma
Cindy S
CS
Li
Qi-Jing
QJ
Parish
Christopher R
CR
Mackay
Charles R
CR
Vinuesa
Carola G
CG
D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics; D005810:Multigene Family; D011485:Protein Binding; D051560:Proto-Oncogene Proteins c-bcl-6; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
C084103:BCL6 protein, human; C490010:Bcl6 protein, mouse; D016207:Cytokines; D004268:DNA-Binding Proteins; D035683:MicroRNAs; D051560:Proto-Oncogene Proteins c-bcl-6; D014157:Transcription Factors