| First Author | Millan AJ | Year | 2019 |
| Journal | J Immunol | Volume | 202 |
| Issue | 8 | Pages | 2296-2306 |
| PubMed ID | 30814306 | Mgi Jnum | J:274339 |
| Mgi Id | MGI:6287874 | Doi | 10.4049/jimmunol.1801157 |
| Citation | Millan AJ, et al. (2019) Sostdc1 Regulates NK Cell Maturation and Cytotoxicity. J Immunol 202(8):2296-2306 |
| abstractText | 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-gamma 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. |
