In vitro activation of lymphocytes with interleukin 2 (IL-2) generates a population of cytotoxic effector cells with broad antitumor activity. However, it is unclear if this recognition is via a heterogeneous population of lymphokine-activated killer (LAK) cells or via a distinct set of select membrane structures common in LAK-sensitive target cells. The investigators' studies indicate that human LAK cells also have the ability to lyse autologous and allogeneic monocytes. In addition, monocyte susceptibility to LAK lysis is found to increase with in vitro culture and differentiation of the monocytes with granulocyte-macrophage colony stimulating factor (GM-CSF) or interleukin 3 (IL-3) further enhances their susceptibility. On the other hand, IFN-gamma is able to downregulate monocyte susceptibility. More importantly, GM-CSF-treated monocytes efficiently compete with tumor cells for LAK lysis suggesting that they may share common NK/LAK recognizable structures. The ability of CSF and IFN-gamma to differentially modulate target susceptibility in monocytes provides a unique opportunity to investigate the target structure(s) recognized by LAK cells on monocytes that might be shared with tumor cells. The questions to be asked are: 1) are known adhesion molecules such as LFA1,2,3, as well as CD16 and CD56 involved in LAK recognition of monocytes? 2) is there a putative NK/LAK target structure other than adhesion molecules involved in initial binding of LAK cells to monocyte? 3) what is the biological significance of LAK lysis of monocytes and is it a means to eliminate unwanted monocytes that have already performed their function such as antigen presentation? 4) is clearance of monocytes via lysis and DNA fragmentation caused by LAK granule components or by autologous enzymes leading to programmed cell death? Work outlined in this proposal should lead to an understanding of the mechanism of LAK recognition of monocytes at the biological, biochemical and molecular levels and give some insight into the role of LAK cells in immunoregulation via control of monocytes and their functions.
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