Engagement of NKG2D by cognate ligand or antibody alone is insufficient to mediate costimulation of human and mouse CD8⁺ T cells

CD8⁺ T cells require a signal through a costimulatory receptor in addition to TCR engagement to become activated. The role of CD28 in costimulating T cell activation is well established. NKG2D, a receptor found on NK cells, CD8⁺ αβ-TCR⁺ T cells, and γδ-TCR⁺ T cells, has also been implicated in T cell costimulation. In this study we have evaluated the role of NKG2D in costimulating mouse and human naive and effector CD8⁺ T cells. Unexpectedly, in contrast to CD28, NK62D engagement by ligand or mAb is not sufficient to costimulate naive or effector CD8⁺ T cell responses in conventional T cell populations. While NKG2D did not costimulate CD8⁺ T cells on its own, it was able to modify CD28-mediated costimulation of human CD8⁺ T cells under certain contitions. It is, therefore, likely that NKG2D acts as a costimulatory molecule only ander restricted conditions or requires additional cofactors.