Aim: High mobility group box-l protein (HMGBI),a ubiquitous nuclear protein,which is recognized as a danger-associated molecular pattern (DAMP) triggering activation of the innate immune system.Previous studies have shown that HMGBI also plays a role in T cell-mediated immunity,but the effect of HMGBI on apoptosis of T cells and its precise mechanism remain to be determined.Methods: Hereto,we show that treatment of Jurkat T cells with recombinant human HMGBI (rhHMGBI) causes a significant dose-dependent increase in percentage of apoptotic cells.Results: When T cells are incubated with HMGBI they express decreased mitochondria fusion-related protein mitofusin-2 (Mfn2) and activate mitochondrial apoptotic pathway via elevation of cytosolic [Ca2+],Bax insertion,and activation of caspase.Furthermore,overexpression of Mfn-2 ameliorates the apoptosis of T cells induced by HMGBI.This occurs at least partly through Mfn2 interaction with Ca2+ release-activated Ca2+ (CRAC) channels proteins Orail and Stiml to keep Ca2+ homeostasis in T cells.Conclusion: Taken together,these data suggest that HMGBI can trigger apoptosis of T lymphocytes through mitochondrial death pathway associated with [Ca2+]i elevation.Mfn2 plays a pivotal role in this process,and it might be a novel therapeutic target in T cell apoptosis related disorders.