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Participation of the CD94 Receptor Complex in Costimulation of Human Natural Killer Cells¹

Stephan D. Voss, John Daley^*, Jerome Ritz^* and Michael J. Robertson^2,*,

^* Division of Hematologic Malignancies, Dana-Farber Cancer Institute; Department of Medicine, Harvard Medical School; Department of Radiology, Beth Israel Deaconess Medical Center, Boston, MA 02115; Bone Marrow Transplant Program, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202

Optimal proliferation and expansion of human NK cells require mitogenic cytokines together with cell contact-dependent costimulation. Production of mAb that can modulate human NK cell proliferation yielded NKH3, which recognizes the CD94 Ag. NKH3 immunoprecipitates contain 70-kDa heterodimeric complexes consisting of a 25-kDa glycoprotein and 40- to 45-kDa molecules. Analysis by two-dimensional isoelectric focusing/SDS-PAGE suggests that several different 40- to 45-kDa species are present in the CD94 receptor complex in human NK cells. NKH3 reacted with essentially all resting NK cells, although CD94 is expressed at higher levels on the CD56^bright (i.e., high level of CD56) CD16^dim/neg (i.e., low level of or absent CD16) subpopulation than on the more abundant CD56^dimCD16^bright NK cell subset. Moreover, the Z199 mAb, which appears to recognize NKG2-A species that can form heterodimers with CD94, stained virtually all CD56^bright NK cells, but only a subset of CD56^dim NK cells. Ligation of CD94 augmented the proliferation of CD56^bright NK cells in response to IL-2 or IL-15 by as much as 10-fold. Secretion of IFN- by CD56^bright NK cells stimulated with IL-2 or IL-15 was also enhanced up to 10-fold after CD94 ligation. CD94 mAb did not consistently costimulate proliferation of or IFN- production by CD56^dim NK cells cultured with IL-2 or IL-15. In contrast, irradiated K562 cells costimulated proliferation of both CD56^bright and CD56^dim NK cells. These results indicate that CD56^bright and CD56^dim NK cells can be costimulated through different receptors, which may allow these distinct NK cell subsets to be independently regulated in vivo.

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