NK cells are innate-like lymphocytes that eliminate virally infected and cancerous cells, but the mechanisms that control NK cell development and cytotoxicity are incompletely understood. We identified roles for sclerostin domain-containing-1 (Sostdc1) in NK cell development and function. Sostdc1-knockout (Sostdc1 ^-/-) mice display a progressive accumulation of transitional NK cells (tNKs) (CD27⁺CD11b⁺) with age, indicating a partial developmental block. The NK cell Ly49 repertoire in Sostdc1 ^-/- mice is also changed. Lower frequencies of Sostdc1 ^-/- splenic tNKs express inhibitory Ly49G2 receptors, but higher frequencies express activating Ly49H and Ly49D receptors. However, the frequencies of Ly49I⁺, G2⁺, H⁺, and D⁺ populations were universally decreased at the most mature (CD27^-CD11b⁺) stage. We hypothesized that the Ly49 repertoire in Sostdc1 ^-/- mice would correlate with NK killing ability and observed that Sostdc1^-/- NK cells are hyporesponsive against MHC class I-deficient cell targets in vitro and in vivo, despite higher CD107a surface levels and similar IFN-γ expression to controls. Consistent with Sostdc1's known role in Wnt signaling regulation, Tcf7 and Lef1 levels were higher in Sostdc1 ^-/- NK cells. Expression of the NK development gene Id2 was decreased in Sostdc1^-/- immature NK and tNK cells, but Eomes and Tbx21 expression was unaffected. Reciprocal bone marrow transplant experiments showed that Sostdc1 regulates NK cell maturation and expression of Ly49 receptors in a cell-extrinsic fashion from both nonhematopoietic and hematopoietic sources. Taken together, these data support a role for Sostdc1 in the regulation of NK cell maturation and cytotoxicity, and identify potential NK cell niches.

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