ICSBP/IRF-8 differentially regulates antigen uptake during dendritic-cell development and affects antigen presentation to CD4+ T cells.
Interferon consensus sequence-binding protein (ICSBP)/interferon regulatory factor 8 (IRF-8) is a transcription factor that plays critical roles in the differentiation of defined dendritic-cell (DC) populations and in the immune response to many pathogens. In this study, we show that splenic DCs (s-DCs) from ICSBP(-/-) mice are markedly defective in their ability to capture and to present exogenous antigens (Ags) to naive CD4(+) T lymphocytes. We found that CD8alpha(+) DCs and, to a lesser extent, CD8alpha(-) DCs from ICSBP(-/-) mice are impaired at internalizing Ags, either through a receptor-mediated pathway or by macropinocytosis, in spite of having a more immature phenotype than their wild-type (WT) counterparts. These features reflected a greatly impaired ability of ICSBP(-/-) s-DCs to present injected soluble ovalbumin (OVA) to OVA-specific CD4(+) T cells in vivo. Conversely, bone marrow (BM)-derived DCs from ICSBP(-/-) mice, in keeping with their immature phenotype, exhibited higher endocytic activity than WT cells. However, Ag-loaded ICSBP(-/-) BM-DCs were defective in priming Ag-specific CD4(+) T lymphocytes and failed to induce a contact hypersensitivity (CHS) response when injected into competent WT hosts. Together, these results indicate that, throughout the developmental program of DCs, ICSBP differentially controls Ag uptake and MHC class II (MHC-II) presentation affecting both functions only in differentiated peripheral DCs.
Mattei
Fabrizio
F
Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy.
Schiavoni
Giovanna
G
Borghi
Paola
P
Venditti
Massimo
M
Canini
Irene
I
Sestili
Paola
P
Pietraforte
Immacolata
I
Morse
Herbert C
HC
Ramoni
Carlo
C
Belardelli
Filippo
F
Gabriele
Lucia
L
D000818:Animals; D017951:Antigen Presentation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D050835:Interferon Regulatory Factors / Q000172:deficiency / Q000276:immunology / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D010873:Pinocytosis; D013154:Spleen / Q000166:cytology; D000099185:Interferon Regulatory Factor-8
D000949:Histocompatibility Antigens Class II; D050835:Interferon Regulatory Factors; D000099185:Interferon Regulatory Factor-8