High-mobility group box 1 promotes NK and DC function as well as crosstalk: studies of selective knockout in immune cells (P2008)

Abstract

Abstract High-mobility group box 1 (HMGB1) is an evolutionarily ancient, highly abundant nuclear protein present in all eukaryotes that has distinct compartmental roles in the nucleus, in the cytosol, and within the extracellular space. Within the nucleus it regulates VDJ recombination in B and T cells as well as promotes access to nuclear hormone/nuclear hormone receptors and p53 and p73 transcriptional complexes. Within the cytosol it promotes and sustains autophagy by displacing Beclin 1 from BCL2 and is critical for mitochondrial quality control. When secreted or released by stressed or necrotic cells, HMGB1 serves as the prototypic Damage Associated Molecular Pattern Molecule (DAMP). We created homozygous floxed HMGB1 mice which deleted exons 2 and 3 in back crossed NKp46-cre or CD11c-cre mice to allow specific deletion in NK or cDC respectively. Loss of HMGB1 in NK cells (NKH-) was associated with diminished number in the spleen, reduced proliferative capacity in response to IL-2 and enhanced tumor growth in a liver metastases model. Conversely loss of HMGB1 in cDC was associated with marked decrease in maturation in response to LPS or CD40 ligation but diminished tumor growth in the same liver model. Markedly decreased maturation of DC by NKH- with decreased CD80, CD86, Class II and CD83 was noted. These studies convincingly demonstrate the critical and central role of HMGB1 in immune regulation.