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 (Treg) play a crucial role in autoimmune diseases and tumor immune escape, the previously unexamined role of HMGB1 on the function of Treg is of great interest. Methods: Human CD4+CD25+CD127- Treg and CD4+CD25-CD127+ conventional T cells (Tcon) 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 Treg and Tcon was investigated. Results: Treg express significantly higher levels of RAGE on the cell surface than Tcon, while levels of TLR4 are similar. HMGB1 modulates Treg biology by inducing migration and prolonging survival. Furthermore, HMGB1 enhances IL-10 release and Treg suppressive capacity in a RAGE-dependent manner. In addition, HMGB1 directly suppresses IFNγ release of Tcon and inhibits their proliferation via TLR4. Conclusion: HMGB1 directly enhances immune inhibitory functions of Treg via RAGE-mediated mechanisms and limits the number and activity of Tcon. HMGB1 effects on Treg may alter immune reactivity in the setting of chronic inflammatory states such as cancer. © The Japanese Society for Immunology. 2012. All rights reserved.