Bcl6 is required for the development of mouse CD4+ and CD8α+ dendritic cells.
Th2-type inflammation spontaneously shown in Bcl6-knockout (KO) mice is mainly caused by bone marrow (BM)-derived nonlymphoid cells. However, the function of dendritic cells (DCs) in Bcl6-KO mice has not been reported. We show in this article that the numbers of CD4(+) conventional DCs (cDCs) and CD8α(+) cDCs, but not of plasmacytoid DCs, were markedly reduced in the spleen of Bcl6-KO mice. Generation of cDCs from DC progenitors in BM cells was perturbed in the spleen of irradiated wild-type (WT) mice transferred with Bcl6-KO BM cells, indicating an intrinsic effect of Bcl6 in cDC precursors. Although cDC precursors were developed in a Bcl6-KO BM culture with Fms-like tyrosine kinase 3 ligand, the cDC precursors were more apoptotic than WT ones. Also p53, one of the molecular targets of Bcl6, was overexpressed in the precursors. The addition of a p53 inhibitor to Bcl6-KO BM culture protected apoptosis, suggesting that Bcl6 is required by cDC precursors for survival by controlling p53 expression. Furthermore, large numbers of T1/ST2(+) Th2 cells were naturally developed in the spleen of Bcl6-KO mice. Th2 skewing was accelerated in the culture of WT CD4 T cells stimulated with Ags and LPS-activated Bcl6-KO BM-derived DCs, which produced more IL-6 and less IL-12 than did WT DCs; the addition of anti-IL-6 Abs to the culture partially abrogated the Th2 skewing. These results suggest that Bcl6 is required in cDC precursors for survival and in activated DCs for modulating the cytokine profile.
Department of Developmental Genetics, Graduate School of Medicine, Chiba University, Chiba, Japan.
Hiromi
H
Ohtsuka
Akemi
A
Sakamoto
Jing
J
Pan
Sumina
S
Inage
Satoshi
S
Horigome
Hirohito
H
Ichii
Masafumi
M
Arima
Masahiko
M
Hatano
Seiji
S
Okada
Takeshi
T
Tokuhisa
D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology / Q000473:pathology / Q000528:radiation effects; D015704:CD4 Antigens / Q000096:biosynthesis* / Q000528:radiation effects; D016827:CD8 Antigens / Q000096:biosynthesis* / Q000528:radiation effects; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology* / Q000528:radiation effects; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000502:physiology* / Q000528:radiation effects; D003713:Dendritic Cells / Q000276:immunology* / Q000528:radiation effects / Q000637:transplantation; D008231:Lymphopenia / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D051560:Proto-Oncogene Proteins c-bcl-6; D013154:Spleen / Q000276:immunology / Q000473:pathology / Q000528:radiation effects
C490010:Bcl6 protein, mouse; D015704:CD4 Antigens; D016827:CD8 Antigens; C409469:CD8 antigen, alpha chain; D004268:DNA-Binding Proteins; D051560:Proto-Oncogene Proteins c-bcl-6