title: HMGB1 conveys immunosuppressive characteristics on regulatory and conventional T cells.
abstract: OBJECTIVE
  The high-mobility group box-1 protein (HMGB1) serves as the prototypic damage-associated molecular pattern molecule, interacting with a variety of defined pattern recognition receptors in the microenvironment of damaged or necrotic tissue. As regulatory T cells (T(reg)) play a crucial role in autoimmune diseases and tumor immune escape, the previously unexamined role of HMGB1 on the function of T(reg) is of great interest.
  
  
  METHODS
  Human CD4(+)CD25(+)CD127(-) T(reg) and CD4(+)CD25(-)CD127(+) conventional T cells (T(con)) were phenotypically analyzed for their constitutive as well as HMGB1-modulated expression of Toll-like receptors (TLR) and the receptor for advanced glycation end products (RAGE). Furthermore, the influence of recombinant and complexed HMGB1 from necrotic cell supernatant on the function of T(reg) and T(con) was investigated.
  
  
  RESULTS
  T(reg) express significantly higher levels of RAGE on the cell surface than T(con), while levels of TLR4 are similar. HMGB1 modulates T(reg) biology by inducing migration and prolonging survival. Furthermore, HMGB1 enhances IL-10 release and T(reg) suppressive capacity in a RAGE-dependent manner. In addition, HMGB1 directly suppresses IFNγ release of T(con) and inhibits their proliferation via TLR4.
  
  
  CONCLUSIONS
  HMGB1 directly enhances immune inhibitory functions of T(reg) via RAGE-mediated mechanisms and limits the number and activity of T(con). HMGB1 effects on T(reg) may alter immune reactivity in the setting of chronic inflammatory states such as cancer.
authors.affiliation: Department of Otorhinolaryngology, University hospital Essen, Hufelandstrasse 55, 45147 Essen, Germany.
authors.forename: Clarissa Anni
authors.initials: CA
authors.lastname: Wild
authors.forename: Christoph
authors.initials: C
authors.lastname: Bergmann
authors.forename: Günter
authors.initials: G
authors.lastname: Fritz
authors.forename: Patrick
authors.initials: P
authors.lastname: Schuler
authors.forename: Thomas K
authors.initials: TK
authors.lastname: Hoffmann
authors.forename: Ramin
authors.initials: R
authors.lastname: Lotfi
authors.forename: Astrid
authors.initials: A
authors.lastname: Westendorf
authors.forename: Sven
authors.initials: S
authors.lastname: Brandau
authors.forename: Stephan
authors.initials: S
authors.lastname: Lang
mesh_terms: D017209:Apoptosis / Q000276:immunology; D002469:Cell Separation; D002470:Cell Survival / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D024243:HMGB1 Protein / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D019139:Tumor Escape / Q000276:immunology
chemical_list: D024243:HMGB1 Protein; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic