Characterization of the recognition and functional heterogeneity exhibited by cytokine‐induced killer cell subsets against acute myeloid leukaemia target cell

Abstract

The polyclonal cytokine-induced killer (CIK) cells exhibit potent cytotoxicity against a variety of tumour cells including autologous and allogeneic acute myeloid leukaemic (AML) targets. At maturity, three lymphocyte subsets: CD3⁻ CD56⁺, CD3⁺ CD56⁻ and CD3⁺ CD56⁺, constitute the bulk of the CIK cell culture. The CD3⁻ CD56⁺ subset behaves like classical natural killer (NK) cells where cytotoxicity is potentiated by blocking the human leucocyte antigen Class I molecules in the AML targets. Both the CD3⁺ CD56⁺ and CD3⁺ CD56⁻ subsets, though known to kill autologous and allogeneic targets to a comparable degree and therefore non-major histocompatibility complex (MHC)-restricted, nevertheless require the presence of the MHC molecule on the target, which interacts with their CD3–T-cell receptor complex. Although CIK cells are often termed ‘NK-like’ T cells, we have demonstrated that the well-characterized NK receptors KIR, NKG2C/E, NKG2D and DNAM-1 are not involved in the process of AML recognition for the CD3⁺ CD56⁻ and CD3⁺ CD56⁺ subsets. The CD3⁺ CD56⁺ and CD3⁺ CD56⁻ subsets express a polyclonal and comparable TCRVβ repertoire in a Gaussian distribution. The CD3⁺ CD56⁺ subset kills AML targets more efficiently than its CD3⁺ CD56⁻ counterpart because of the presence of a higher proportion of CD8⁺ cells. The CD3⁺ CD56⁺ subset comprise more terminally differentiated late effector T cells that bear the CD27⁺ CD28⁻ or CD27⁻ CD28⁻ phenotype, with a higher granzyme A content. In comparison, the phenotype of the CD3⁺ CD56⁻ subset is consistent with early effector T cells that are CD27⁺ CD28⁺ and CD62L⁺, known to be less cytotoxic but possess greater proliferative potential.