Granulysin expressed in a humanized mouse model induces apoptotic cell death and suppresses tumorigenicity

Abstract

Granulysin (GNLY) is a cytolytic and proinflammatory protein expressed in activated human cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. Conventional mouse models cannot adequately address the triggering mechanism and immunopathological pathways in GNLY-associated diseases due to lack of the GNLY gene in the mouse genome. Therefore, we generated a humanized immune system (HIS) mouse model by transplanting human umbilical cord blood mononuclear cells into NOD.Cg-Prkdc^scid Il2rg^tm1Wjl/SzJ (NSG) mice after sublethally irradiation. We examined the GNLY expression and its effects on tumor growth using this system. Our HIS mice expressed human CD45⁺, CD4⁺, CD8⁺ and CD56⁺ cells in the peripheral blood and spleen. A high expression level of human Th1/Th2 and NK cytokines was detected, indicating the activation of both T and NK cells. Importantly, we found an elevated level of GNLY in the serum and it was produced by human CTLs and NK cells obtained from the peripheral blood mononuclear cells and spleen cells in the HIS mice. The serum level of GNLY was negatively correlated with the proliferation of transplanted tumor cells in HIS mice. Collectively, our findings strongly supported that HIS mouse as a valuable model for studying human cancer under an intact immune system and the role of GNLY in tumorigenesis.