Defining the roles of NKG7 expressed by CD4 ⁺ and CD8 ⁺ T cells during malaria

Malaria, caused by Plasmodium parasites, is a significant global health issue. CD4 ⁺ and CD8 ⁺ T cells are important for immunity against Plasmodium infections, but the specific roles of many immune-related effector molecules in T cells remain poorly defined. Here, we investigated the function of NK cell granule protein 7 (NKG7) in T cells during malaria, focusing on its role in CD4 ⁺ and CD8 ⁺ T cells in Plasmodium blood-stage responses. In a non-lethal malaria model, NKG7 played a protective role in CD4 ⁺ T cell responses, affecting pro-inflammatory T helper 1 (Th1), IL-10-producing type 1 regulatory (Tr1), and T follicular helper cell development. In a model of cerebral malaria, NKG7 was shown to have a cell-intrinsic role in CD4 ⁺ T cells for perforin and granzyme B expression, as well as the development of Tr1 cells. Human investigations involving peripheral blood mononuclear cells from volunteers participating in controlled human P. falciparum malaria infection studies, as well as endemic country patients with P. falciparum and P. vivax malaria, corroborated these findings. High NKG7 expression in T cells from Plasmodium -infected humans was observed, as well as differences in NKG7 expression based on the infecting Plasmodium species. NKG7 expression was associated with both cytotoxic and non-cytotoxic T cells, indicating varied functions following infection. These results advance our understanding about NKG7’s role in T cell-mediated malaria immunity and suggest potential for targeting NKG7 to improve outcomes following Plasmodium infection.