Nuclear HMGB1 is critical for CD8 T cell IFN-γ production and anti-tumor immunity

HMGB1 (high-mobility group box-1) has been extensively studied as a damage-associated molecular pattern, with secreted cytokine function. However, its regulation on T cells, especially the function in the nucleus, has not been elucidated. Here, we use conditional knockout (HMGB1-f/f; CD2-cre) mice and find that HMGB1 potentiates the proliferation and interferon gamma (IFN-γ) expression of CD8 T cells rather than CD4 T cells. Notably, nuclear, but not secreted, HMGB1 supports the expression of IFN-γ in CD8 T cells via directly regulating the activity of Eomes, the transcription factor for IFN-γ. Functional study shows that HMGB1 promotes the anti-tumor ability of CD8 T cells in vitro and in vivo. Finally, tumor environmental interleukin-7 promotes HMGB1 and IFN-γ production via fatty acid oxidation in CD8 T cells. Overall, we identify the role of nuclear HMGB1 in CD8 T cell differentiation and demonstrate that it plays an important role in the anti-tumor programs of CD8 T cells.