2Rb (37), gc (38, 39), or Jak3 (40–42), which are receptor or signaling components for both IL-2 and IL-15. Interest- ingly, although IL-2 potently augments NK cytolytic activ- ity, the fact that IL-22/2 mice have NK cells indicates that IL-2 is not absolutely required for NK cell development. Instead, IL-15 has been implicated as playing an important role in NK cell development (43–46). Supporting this con- cept, the absence of NK cells in IRF12/2 mice has been correlated with defective IL-15 production (47). Our data now reveal a partial decrease in NK cells in both Stat5a2/2 and Stat5b2/2 mice, indicating that Stat5 activation is vital for normal NK cell development. Interestingly, although diminished NK cells were seen in both Stat5a2/2 and Stat5b2/2 mice, it was only the NK cells from Stat5b2/2 mice that exhibited a dramatic defect in their ability to respond to IL-2 and IL-15 (Fig. 3, D and E), and only Stat5b2/2 mice that had a lower percentage of NK cells expressing IL-2Rb (Fig. 3 F). The basis for this decrease in IL-2Rb1 NK cells remains unclear; although a number of transcription factors including early growth re- sponse (Egr)-1, Ets-1, and GABP have been shown to be important for IL-2Rb promoter activity (48, 49), a Stat5b- dependent response element for this gene has not been reported. The decrease in perforin mRNA in IL-2– and IL-15–treated Stat5b2/2 splenocytes is consistent with per- forin being a Stat5b-regulated gene. In conclusion, just as Stat4 and Stat6, respectively, are important for normal Th1 and Th2 cell development and function (6–10), our results reveal that both Stat5a and Stat5b contribute to normal NK cell development with a greater defect being seen particularly for NK function in Stat5b2/2 mice. Although Stat5a and Stat5b have similar (but not identical) binding activities in vitro and can both drive expression of similar reporter constructs in transfected cells, the data presented here are consistent with published studies suggesting differential roles for these proteins in nonlymphoid settings in vivo (20–22). It will be vital to further clarify the range of target genes that are controlled by Stat5a and Stat5b. We have shown that IL-2Ra is defec- tive in the absence of either Stat5 protein, whereas IL-2Rb and perforin appear more dependent on Stat5b. Moreover, by demonstrating that Stat5b plays a particularly critical role for proliferation and cytolytic activity of NK cells, we now provide a key example of different biological roles for these two Stat5 proteins within the immune system. We thank Drs. Lothar Hennighausen, Xiuwen Liu, and Anthony Wynshaw-Boris (National Institutes of Health [NIH]) for Stat5a2/2 mice, and Dr. Alex Grinberg (NIH) for thawing and implanting Stat5b2/2 fro- zen embryos. We thank Dr. Thomas R. Malek (University of Miami, Miami, FL) for the murine IL-2Rb cDNA; Drs. Grace Ju and John Hakimi (Hoffmann-La Roche) for recombinant IL-2; Dr. James E. Darnell, Jr. (The Rockefeller University, New York, NY) for pHe7 cDNA; Dr. William E. Paul (NIH) for murine IL-4; and Drs. Dana P. Ascherman and Robert D. Schreiber for valuable discussions/critical comments. K. 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