Sostdc1 Regulates NK Cell Maturation and Cytotoxicity

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.