PubMed · 7289089
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T Suzuta. 1981. [ADCC test].. https://pubmed.ncbi.nlm.nih.gov/7289089/
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Chemokines have been shown to play an important role in both the adhesion and migration of numerous leukocytic cell types, including granulocytes, monocytes, mast cells, and T lymphocytes. However, the biologic effects of chemokines on NK cells remain to be defined. Chemotaxis studies using purified human NK cells and a panel of human recombinant chemokines revealed that macrophage inflammatory protein (MIP)-1 alpha and IFN-inducible protein-10 (IP-10) are potent NK cell chemoattractants in vitro. Modest but significant chemotactic (not chemokinetic) responses were also observed in response to RANTES, MCP-1, MCP-2, MCP-3, and MIP-1 beta. Chemokine receptor expression on human NK cells was determined through displacement and Scatchard analyses, using a panel of radiolabeled chemokines, and revealed the presence of both distinct and shared chemokine receptors with affinities similar to those previously described for other cell types. Functional studies have also revealed that the beta chemokines and IP-10 are capable of augmenting NK- but not LAK- or ADCC-specific cytolytic responses in both a dose- and donor-dependent fashion. Neutralization analysis using Abs specific for various adhesion molecules revealed that NK:tumor cell conjugate formation is required for chemokine-induced NK killing. In addition, NK cells incubated in the presence of beta chemokines and IP-10 for 4 h induced the release of granule-derived serine esterases, suggesting a possible mechanism for chemokine-mediated NK killing. These results suggest that chemokines not only play an important role in the recruitment of NK cells, but also may be important mediators of NK cell degranulation augmenting local tumor cell destruction.
Using our recently developed target system model of env gene-transfected cells for gp120/41-specific antibody-dependent cellular cytotoxicity (ADCC) assays, we evaluated the ADCC effector function of the peripheral blood mononuclear cells (PBMC) in 39 human immunodeficiency virus type 1 (HIV-1)-infected individuals. The natural killer (NK) activity of the PBMC from these individuals against K562 was also determined. A significant positive correlation (p < or = 0.05, r = 0.37) was found between these two activities. On the basis of our data, we built a regression equation for the two activities whereby the ADCC effector function of PBMC of an HIV-infected individual can be predicted from their NK activity. We also found that the endpoint titer of a given serum for ADCC-mediating antibodies in the ADCC assay varied depending on the NK activity of the effector cells used: The effectors with high NK activity tended to give higher titers as compared with the effectors with low NK activity. To our knowledge, this is the first formal documentation of the existence of a positive correlation between the ADCC and NK activities of the PBMC. It also shows that the ADCC titer of serum in ADCC assay may vary depending on the NK activity of the effector cells used. This observation underscores an important variable of ADCC assays. Using our statistical model, one can predict the ADCC effector function of the PBMC from HIV-infected individuals from their NK activity and thus help clarify the role of this important immune response in HIV infection and AIDS prognosis.
Chimeric receptors in which a signaling component of the TCR complex such as zeta is fused directly to the ligand binding domain of a heterologous receptor or Ab have been shown to redirect the specific effector activity of T lymphocytes. We previously described the ability of two classes of such chimeric zeta-receptors bearing extracellular domains derived from either the HIV receptor CD4 (CD4 zeta) or an HIV-specific single chain Ab to redirect primary human CD8+ T cells to kill HIV-infected T cells. In this report we demonstrate that human NK cells can be genetically modified to express high levels of CD4 zeta using retroviral transduction. The CD4 zeta chimeric receptor is biochemically active, as cross-linking of CD4 zeta on NK cells results in tyrosine phosphorylation of CD4 zeta and multiple cellular proteins. More importantly, the CD4 zeta chimeric receptor is functionally active and can direct NK cells to specifically and efficiently lyse either NK-resistant tumor cells expressing the relevant ligand, gp120, or CD4+ T cells infected with HIV. These results show that human NK cells can be readily activated via zeta-based chimeric receptors to target both tumor and virally infected cells, and suggest a novel approach to the treatment of disease.