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. 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.

danger signals, immunosuppression, RAGE, TLR4, tolerance