Beschreibung:
<jats:title>Abstract</jats:title>
<jats:p>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. Conclusion: 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.</jats:p>