Sostdc1 regulates natural killer cell maturation and cytotoxicity

Abstract

Abstract Natural killer (NK) cells are specialized lymphocytes with innate ability to eliminate virally infected and cancerous cells, but the mechanisms that control NK cell development and cytotoxicity are incompletely understood. We identified novel roles for sclerostin domain containing-1 (Sostdc1) in NK cell development and function. Sostdc1-knockout (KO) mice display a progressive accumulation of transitional NK cells (CD27+CD11b+, tNK) with age, indicating a partial developmental block. The Ly49 repertoire on NK cells in KO mice is also changed. Lower frequencies (%) of KO splenic tNKs express inhibitory Ly49G2, but higher % of activating Ly49H+ and D+ cells. However, the % of Ly49I+, G2+, H+ and D+ populations were universally decreased at the most mature (CD27− CD11b+, mNK) stage. We hypothesized that the Ly49 repertoire in Sostdc1-KO mice would correlate with NK killing ability. We observed that KO NK cells are hyporesponsive against MHC-I-deficient cell targets in vitro and in vivo, despite higher CD107a surface levels and similar IFN-gamma expression to controls. Further investigation is required to determine Sostdc1’s role in NK cell cytotoxicity and self/non-self recognition. Sostdc1 is expressed in the bone periosteum, and we discovered Sostdc1 expression in NK cells. Consistent with this, reciprocal BM transplant experiments showed that Sostdc1 regulates NK cells through cell-extrinsic and cell-intrinsic manners. Transcriptomic profiling should identify if Sostdc1’s known roles in Wnt and BMP signaling are active, and reveal novel effects of Sostdc1 on NK cells. Taken together, these data support a role for Sostdc1 in the regulation of NK cell maturation, and NK cell cytotoxicity, and identify potential NK cell niches.