MHC Class Ia Empowers MHC Class Ib-restricted CD8+ T Cells with Strong Tumoricidal Capacity

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.

Role of a selecting ligand in shaping the murine γδ-TCR repertoire

Unlike αβ-T lineage cells, where the role of ligand in intrathymic selection is well established, the role of ligand in the development of γδ-T cells remains controversial. Here we provide evidence for the role of a bona fide selecting ligand in shaping the γδ-T cell-receptor (TCR) repertoire. Reactivity of the γδ-TCR with the major histocompatibility complex (MHC) Class Ib ligands, H2-T10/22, is critically dependent upon the EGYEL motif in the complementarity determining region 3 (CDR3) of TCRδ. In the absence of H2-T10/22 ligand, the commitment of H2-T10/22 reactive γδ-T cells to the γδ fate is diminished, and the specification of those γδ committed cells to the IFN-γ or interleukin-17 effector fate is altered. Furthermore, those cells that do adopt the γδ fate and mature exhibit a profound alteration in the γδTCR repertoire, including depletion of the EGYEL motif and reductions in both CDR3δ length and charge. Taken together, these data suggest that ligand plays an important role in shaping the TCR repertoire of γδ-T cells.

Intraepithelial CD94+ tumor-infiltrating lymphocytes in a context of HLA-E overexpression as a new immune checkpoint to predict prognosis in colorectal carcinomas.

e14592 Background: A better understanding of the immune-modulating interactions between tumor cells and immune cells underlying the balance between immune control and immune resistance in colorectal cancer (CRC) is crucial for the design of immunotherapies. We have previously demonstrated that overexpression of the human MHC class Ib molecule - HLA-E/β2 microglobulin - by tumor cells in CRC was associated with an unfavorable prognosis, suggesting its involvement in immune escape. However, the specific receptor of HLA-E/β2m - CD94/NKG2A, inhibitory or CD94/NKG2C, activating - expressed by tumor-infiltrating lymphocytes (TIL), as well as the influence of the microsatellite status in HLA-E/β2m overexpression, remain unknown. Methods: We investigated in the primary tumor of 245 CRC patients 1) the association of HLA-E/β2m overexpression and the density of CD94+ intraepithelial TIL (IEL-TIL) with the microsatellite status, 2) the nature of CD94+ TIL and the receptor expressed - CD94/NKG2A or CD94/NKG2C - and 3) the prognostic influence of CD94+ IEL-TIL. Results: HLA-E/β2m was preferentially overexpressed in MSI compared with MSS CRC (44,6 % vs 18,4 % respectively, p = 0.0001), and significantly associated with a high density of CD94+ IEL-TIL in MSI (0,9% in HLA-E/β2m+ vs 0,2% in HLA-E/β2m– CRC, p = 0,001), and in MSS CRC (0,38% vs 0,15%, p < 0,0001). These CD94+ TIL mostly corresponded to CD8+ αβ T cells preferentially expressing the inhibitory NKG2A chain. Finally, a high density of CD94+ IEL-TIL was independently associated with a worse OS (p = 0.03). Conclusions: These results strongly suggest that HLA-E/β2m - CD94/NKG2A interactions, preferentially up-regulated in MSI CRC, represent a promising inhibitory immune checkpoint. From a clinical point of view, this inhibitory immune checkpoint could be blocked by the new anti-NKG2A monoclonal antibody.