MHC Class Ib-restricted CD8+ T Cells Possess Strong Tumoricidal Activities

The tumoricidal effects of CD8+T cells are well acknowledged, but how MHC Ib-restricted CD8+T (Ib-CD8+T) cells contribute to anti-tumor immunity remains obscure. Here, we show that infusion of MHC Ia+ cells to Kb-/-Db-/- mice induced the expansion of Ib-CD8+T cells in tumors and potently inhibited tumor progression. Such priming of Ib-CD8+T cells by MHC-Ia is not MHC haplotype restricted and MHC Ia tetramers alone can prime Ib-CD8+T cells for activation. The MHC Ia priming promoted Tbet expression in Ib-CD8+T cells and in absence of Tbet, such priming effect diminished. Importantly, these tumoricidal Ib-CD8+T cells are positive for CX3CR1, and exhibit rapid proliferation, high expression of cytotoxic factors, and prolonged persistence at tumor sites. Adoptive transfer of CX3CR1+Ib-CD8+T cells to wild type mice resulted in potent anti-tumor effects. Our findings unravel an uncharacterized function of MHC Ia molecules in immunoregulation and raise the possibility of using Ib-CD8+T cells in tumor immunotherapy. Single cell RNA seq of CD8+ T cells isolated from tumor or spleen of C57 or Kb-/-Db-/- mice treated with MHC Ia+MCs or MHC Ia-MCs. Kb-/-Db-/- mice and C57BL/6 mice were i.v. injected with B16F10 cells (3× The tumor bearing Kb-/-Db-/- mice were i.p. injected with Ia-MSCs (1×or Ia+MSCs (1×every 3 days starting on day 0. After 9 days, splenic CD8+ T cells from Ia-MSCs treated Kb-/-Db-/- mice (Ia-MSCs-spleen), splenic CD8+ T cells from Ia+MSCs treated Kb-/-Db-/- mice (Ia+MSCs-spleen), tumor infiltrated CD8+ T cells from Ia+MSCs treated Kb-/-Db-/- mice (Ia+MSCs-tumor), splenic CD8+ T cells from C57BL/6 mice (C57BL/6-spleen), and tumor infiltrated CD8+ T cells from C57BL/6 mice (C57BL/6-tumor) were isolated using magnet beads and subjected to single cell RNA sequencing. *** Submitter was unable to provide valid raw data files for the following samples: GSM5005586 GSM5005589 GSM5005590.