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NK Cells Play a Critical Role in the Regulation of Class I-Deficient Hemopoietic Stem Cell Engraftment: Evidence for NK Tolerance Correlates with Receptor Editing¹

Yiming Huang^*, Francine Rezzoug^*, Hong Xu^*, Paula M. Chilton^*, Carrie L. Schanie^*, Isabelle Fugier-Vivier^*, and Suzanne T. Ildstad^2,*,

^* Institute for Cellular Therapeutics, University of Louisville, Louisville, KY 40202; and Department of Surgery, University of Louisville, Louisville, KY 40202

The role that NK cells play in the rejection of hemopoietic stem cell (HSC) and tolerance induction has remained controversial. In this study, we examined whether NK cells play a direct role in the rejection of HSC. Purified HSC from MHC class II-deficient mice engrafted readily in congenic mice, while HSC from class I-deficient donors (₂-microglobulin^–/– (₂m^–/–)) failed to engraft. Recipient mice lacking CD8⁺, CD4⁺, or T cells also rejected HSC from class I-deficient donors, pointing directly to NK cells as the effector in rejection of HSC. Recipients, deficient in or depleted of NK cells, engrafted readily with ₂m^–/– HSC. Expression of the activating Ly-49D and inhibitory Ly-49G2 receptors on recipient NK cells was significantly decreased in these ₂m^–/–B6 chimeras, and the proportion of donor NK cells expressing Ly-49D was also significantly decreased. Notably, ₂m^–/– chimeras accepted ₂m^–/– HSC in second transplants, demonstrating that NK cells in the chimeras had been tolerized to ₂m^–/–. Taken together, our data demonstrate that NK cells play a direct role in the regulation of HSC engraftment, and down-regulation and/or deletion of specific NK subsets in mixed chimeras can contribute to the induction of NK cell tolerance in vivo. Moreover, our data show that bone marrow-derived elements significantly contribute to NK cell development and tolerance.

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