MHC class Ib-restricted CD8 T cells possess strong tumoricidal activities.

The importance of classical CD8 T cells in tumor eradication is well acknowledged. However, the anti-tumor activity of MHC (major histocompatibility complex) Ib-restricted CD8 T (Ib-CD8 T) cells remains obscure. Here, we show that CX3CR1-expressing Ib-CD8 T cells (Ib-restricted CD8 T cells) highly express cytotoxic factors, austerely resist exhaustion, and effectively eliminate various tumors. These Ib-CD8 T cells can be primed by MHC Ia (MHC class Ia molecules) expressed on various cell types for optimal activation in a Tbet-dependent manner. Importantly, MHC Ia does not allogeneically activate Ib-CD8 T cells, rather, sensitizes these cells for T cell receptor activation. Such effects were observed when MHC Ia cells were administered to tumor-bearing KDmice. A similar population of tumoricidal CX3CR1CD8 T cells was identified in wild-type mice and melanoma patients. Adoptive transfer of Ib-CD8 T cells to wild-type mice inhibited tumor progression without damaging normal tissues. Taken together, we demonstrate that MHC class Ia can prime Ib-CD8 T cells for robust tumoricidal activities.