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The Journal of Immunology, 2004, 173: 6547-6563.
Copyright © 2004 by The American Association of Immunologists

Novel Insights on Human NK Cells’ Immunological Modalities Revealed by Gene Expression Profiling1

Jacob Hanna*, Pamela Bechtel{dagger}, Yufeng Zhai{dagger}, Fadi Youssef*, Karen McLachlan{dagger} and Ofer Mandelboim2,*

* The Lautenberg Center for General and Tumor Immunology, Hebrew University-Hadassah Medical School, Jerusalem, Israel; and {dagger} Biogen Idec, San Diego, CA 92191

As part of the innate immune system, human NK cells play a critical role early in the systemic host defense against pathogens and tumor cells. Recent studies suggest a more complex view of NK cell behavior, as different functions and tissue localizing capabilities seem to be preferentially assigned to distinct subpopulations of NK cells, CD56dimCD16+ or CD56brightCD16–. In this study, we used oligonucleotide microarrays to compare the expression profile of ~20,000 genes in three NK cell subpopulations: peripheral blood-derived CD56dimCD16+, CD56brightCD16–, and in vitro-activated CD16+ NK cells. The differential expression of selected genes was verified by flow cytometry and functional assays. When comparing CD56dimCD16+ and CD56brightCD16– subsets, a new heterogeneous molecular basis for the functional and developmental differences between these two subsets was revealed. Furthermore, systematic analysis of transcriptional changes in activated CD16+ NK cells provided us with a better understanding of NK function in inflamed tissues. We highlight a number of genes that were overexpressed upon activation (e.g., OX40 ligand, CD86, Tim3, galectins, etc.), that enable these cells to directly cross-talk with other innate and adaptive immune effectors. The overexpressed genes assign novel intriguing immunomodulatory functions to activated NK cells, in addition to their potent cytotoxic abilities.




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