Sostdc1 Regulates NK Cell Maturation and Cytotoxicity

Abstract

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 (<i>Sostdc1</i>) in NK cell development and function. <i>Sostdc1</i>-knockout (<i>Sostdc1</i> ^-/-) 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 <i>Sostdc1</i> ^-/- mice is also changed. Lower frequencies of <i>Sostdc1</i> ^-/- 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 <i>Sostdc1</i> ^-/- mice would correlate with NK killing ability and observed that <i>Sostdc1^-/-</i> 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, <i>Tcf7</i> and <i>Lef1</i> levels were higher in <i>Sostdc1</i> ^-/- NK cells. Expression of the NK development gene <i>Id2</i> was decreased in <i>Sostdc1^-/-</i> immature NK and tNK cells, but <i>Eomes</i> and <i>Tbx21</i> expression was unaffected. Reciprocal bone marrow transplant experiments showed that <i>Sostdc1</i> 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 <i>Sostdc1</i> in the regulation of NK cell maturation and cytotoxicity, and identify potential NK cell niches.