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

Abstract

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 K^b-/-D^b-/-mice. A similar population of tumoricidal CX3CR1⁺CD8⁺ 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.