Release of high mobility group box 1 by dendritic cells controls T cell activation via the receptor for advanced glycation end products.
High mobility group box 1 (HMGB1) is an abundant and conserved nuclear protein that is released by necrotic cells and acts in the extracellular environment as a primary proinflammatory signal. In this study we show that human dendritic cells, which are specialized in Ag presentation to T cells, actively release their own HMGB1 into the extracellular milieu upon activation. This secreted HMGB1 is necessary for the up-regulation of CD80, CD83, and CD86 surface markers of human dendritic cells and for IL-12 production. The HMGB1 secreted by dendritic cells is also required for the clonal expansion, survival, and functional polarization of naive T cells. Using neutralizing Abs and receptor for advanced glycation end product-deficient (RAGE(-/-)) cells, we demonstrate that RAGE is required for the effect of HMGB1 on dendritic cells. HMGB1/RAGE interaction results in downstream activation of MAPKs and NF-kappaB. The use of an ancient signal of necrosis, HMGB1, by dendritic cells to sustain their own maturation and for activation of T lymphocytes represents a profitable evolutionary mechanism.
Dumitriu
Ingrid E
IE
Cancer Immunotherapy and Gene Therapy Program, Clinical Immunology Unit, H. San Raffaele Scientific Institute, Milan, Italy.
Baruah
Paramita
P
Valentinis
Barbara
B
Voll
Reinhard E
RE
Herrmann
Martin
M
Nawroth
Peter P
PP
Arnold
Bernd
B
Bianchi
Marco E
ME
Manfredi
Angelo A
AA
Rovere-Querini
Patrizia
P
D021581:Active Transport, Cell Nucleus / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D002999:Clone Cells; D018920:Coculture Techniques; D003600:Cytosol / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D005110:Extracellular Space / Q000378:metabolism; D006131:Growth Inhibitors / Q000494:pharmacology; D024243:HMGB1 Protein / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D007106:Immune Sera / Q000494:pharmacology; D018664:Interleukin-12 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000502:physiology*; D016328:NF-kappa B / Q000502:physiology; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism*; D016192:Resting Phase, Cell Cycle / Q000502:physiology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000502:physiology*; D018417:Th1 Cells / Q000166:cytology / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology
D006131:Growth Inhibitors; D024243:HMGB1 Protein; D007106:Immune Sera; D016328:NF-kappa B; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D018664:Interleukin-12; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases