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.
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:HumanCD4(+)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.
Authors: Sujun Chen; Guanghui Zhu; Yue Yang; Fubo Wang; Yu-Tian Xiao; Na Zhang; Xiaojie Bian; Yasheng Zhu; Yongwei Yu; Fei Liu; Keqin Dong; Javier Mariscal; Yin Liu; Fraser Soares; Helen Loo Yau; Bo Zhang; Weidong Chen; Chao Wang; Dai Chen; Qinghua Guo; Zhengfang Yi; Mingyao Liu; Michael Fraser; Daniel D De Carvalho; Paul C Boutros; Dolores Di Vizio; Zhou Jiang; Theodorus van der Kwast; Alejandro Berlin; Song Wu; Jianhua Wang; Housheng Hansen He; Shancheng Ren Journal: Nat Cell Biol Date: 2021-01-08 Impact factor: 28.824
Authors: Samantha A Chalmers; Alec S Eidelman; Jason C Ewer; Jacob M Ricca; Antonio Serrano; Kyle C Tucker; Caroline M Vail; Robert A Kurt Journal: Cell Immunol Date: 2013-05-14 Impact factor: 4.868
Authors: N Islam; M Whitehouse; S Mehendale; M Hall; J Tierney; E O'Connell; A Blom; G Bannister; J Hinde; R Ceredig; B A Bradley Journal: Clin Exp Immunol Date: 2014-08 Impact factor: 4.330