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. 1996 Jul;88(3):428–440. doi: 10.1046/j.1365-2567.1996.d01-668.x

HL-60 myeloid leukaemia cells acquire immunostimulatory capability upon treatment with retinoic acid: analysis of the responding population and mechanism of cytotoxic lymphocyte activation.

S M Geary 1, L K Ashman 1
PMCID: PMC1456359  PMID: 8774361

Abstract

HL-60 myeloid leukaemia cells are ineffective as stimulators of allogeneic lymphocytes in mixed leucocyte culture (MLC). These cells can be induced to differentiate along the monocytic or granulocytic pathways with or without acquisition of major histocompatibility complex (MHC) class II antigen by various agents. Surprisingly, treatment of HL-60 cells with 10 nM all-trans retinoic acid (RA) for 7 days (HL-60-R7) resulted in a marked increase in MLC stimulation although the cells lacked detectable MHC class II antigen expression at the initiation of the MLC. In contrast, treatment with interferon-gamma (IFN-gamma), with or without RA, induced MHC class II antigen expression but failed to enhance MLC stimulation. Lymphocytes responding to HL-60-R7 were predominantly CD8+ and/or CD16+ and displayed enhanced cytolytic capacity for HL-60 and HL-60-R7 cells as well as natural killer (NK)-sensitive K562 cells. Nevertheless, monoclonal antibodies (mAb) to MHC class II antigens substantially inhibited the MLC and some CD4+ lymphocytes in the responding population were required, although this requirement could be replaced by the addition of interleukin-2 (IL-2). HL-60-R7 (and HL-60) cells were shown to acquire detectable MHC class II antigen expression during the first 3 days of the MLC. Thus a low level of activation by MHC class II+ stimulator cells appears to be required for the response. Analysis of the role of cytokines with costimulatory activity for T cells and/or NK cells indicated that tumour necrosis factor-alpha (TNF-alpha) was important in the proliferative response, while interleukins-1, -6 and -12 and stem cell factor did not seem to be involved. Cell interaction molecules lymphocyte function-associated antigen-1 (LFA-1) (CD11a), intracellular adhesion molecule-1 (ICAM-1) (CD54), ICAM-3 (CD50) and B7.2 (CD86) were up-regulated on HL-60-R7. Blocking mAb to LFA-1 and B7.2 potently inhibited the proliferative response indicating a key role for these molecules in the enhanced immunostimulation by HL-60-R7 cells. The results may have implications for the mechanism of the therapeutic effect of RA in acute promyelocytic leukaemia and may also provide valuable information in regard to the immunogenicity of tumour cells in general.

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Selected References

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