EBV-Induced Human CD8⁺ NKT Cells Synergise CD4⁺ NKT Cells Suppressing EBV-Associated Tumours Upon Induction of Th1-Bias

Abstract

CD8⁺ natural killer T (NKT) cells from EBV-associated tumour patients are quantitatively and functionally impaired. EBV-induced CD8⁺ NKT cells drive syngeneic T cells into a Th1-bias response to suppress EBV-associated malignancies. IL-4-biased CD4⁺ NKT cells do not affect either syngeneic T cell cytotoxicity or Th cytokine secretion. Circulating mDC1 cells from patients with EBV-associated malignancies impair the production of IFN-γ by CD8⁺ NKT cells. In this study, we have established a human-thymus-SCID chimaera model to further investigate the underlying mechanism of EBV-induced CD8⁺ NKT cells in suppressing EBV-associated malignancies. In the human-thymus-SCID chimera, EBV-induced CD8⁺ NKT cells suppress EBV-associated malignancies in a manner dependent on the Th1-bias response and syngeneic CD3⁺ T cells. However, adoptive transfer with CD4⁺ NKT cells alone inhibits T cell immunity. Interestingly, CD4⁺ NKT cells themselves secrete high levels of IL-2, enhancing the persistence of adoptively transferred CD8⁺ NKT cells and T cells, thereby leading to a more pronounced T cell anti-tumour response in chimaeras co-transferred with CD4⁺ CD8⁺ NKT cells. Thus, immune reconstitution with EBV-induced CD4⁺ and CD8⁺ NKT cells synergistically enhances T cell tumour immunity, providing a potential prophylactic and therapeutic treatment for EBV-associated malignancies.