Abstract: Objective To investigate the effect of tumor necrosis factor-α-induced protein 8 like-2 (TIPE2) on apoptosis of CD4+ T lymphocytes in a murine model of severe burn injury. Methods A total of 140 male mice were randomly allocated into 6 groups. Small RNA interference technique was used to construct a siTIPE2-overexpressing lentivirus, and severe burn injury models were established in the mice. CD4+ T cells were purified from spleen of the mice, and the expressions of TIPE2, Smad2/ Smad3, P-Smad2/P-Smad3 and Bcl-2/Bimprotein in CD4 + Tregs were detected. The changes in mitochondrial membrane potential and cytochrome C in CD4 + T cells were detected, and the activities of caspase-3, caspase-8, and caspase-9 were analyzed. Results Down-regulation of TIPE2 promoted the apoptosis of CD4+ T lymphocytes in siTIPE2-burn group, in which the protein expressions of P-smad2/P-Smad3 decreased, Bcl-2 expression increased and Bim expression decreased significantly as compared with the other groups (P<0.01 or 0.05). The mitochondrial membrane potential and cytochrome C expression in CD4 + T cells were down-regulated in siTIPE2-burn group (P<0.05) with a lowered caspase-3 activity compared with TIPE2-burn group (P<0.01) and decreased caspase-8 and caspase-9 compared with the other groups (P<0.05). The apoptosis rate was the highest in TIPE2-burn group, whose Smad2/Smad3 was higher than that in the sham group (P<0.05) and the expression of P-smad2/P-Smad3 significantly increased compared with the other groups (P<0.05). In TIPE2-burn group, the mitochondrial membrane potential in CD4+ T cells was decreased (P<0.01), the expression of cytochrome C increased markedly (P<0.01), and the activities of caspase-3, caspase-8, and caspase-9 were all obviously higher than those in the other groups (P< 0.05). Conclusions As an important immunoregulatory molecule, TIPE2 can promote the apoptosis of CD4+T lymphocyte in mice with sever burn injury.