PARTICIPATION OF THE CD94 RECEPTOR COMPLEX IN COSTIMULATION OF HUMAN NATURAL-KILLER-CELLS

Optimal proliferation and expansion of human NK cells require mitogeni c cytokines together with cell contact-dependent costimulation. Produc tion of mAb that can modulate human NK cell proliferation yielded NKH3 , which recognizes the CD94 Ag, NKH3 immunoprecipitates contain simila r to 70-kDa heterodimeric complexes consisting of a similar to 25-kDa glycoprotein and similar to 40- to 45-kDa molecules. Analysis by two-d imensional isoelectric focusing/SDS-PAGE suggests that several differe nt 40- to 45-kDa species are present in the CD94 receptor complex in h uman NK cells. NKH3 reacted with essentially all resting NK cells, alt hough CD94 is expressed at higher levels on the CD56(bright) (i.e., hi gh level of CD56) CD16(dim/neg) (i.e., low level of or absent CD16) su bpopulation than on the more abundant CD56(dim)CD16(bright) NK cell su bset. Moreover. the Z199 mAb, which appears to recognize NKG2-A specie s that can form heterodimers with CD94, stained virtually all CD56(bri ght) NK cells, but only a subset of CD56(dim) NK cells. Ligation of CD 94 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-gamma by CD56(b right) 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-gamma production by CD56(dim) NK cells cultur ed with IL-2 or IL-15. In contrast, irradiated K562 cells costimulated proliferation of both CD56(bright) and CD56(dim) NK cells. These resu lts indicate that CD56(bright) and CD56(dim) NK cells can be costimula ted through different receptors, which may allow these distinct NK cel l subsets to be independently regulated in vivo.