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bioRxiv · 10.1101/387225

Sostdc1 regulates natural killer cell maturation and cytotoxicity

Millan, A. J.·Elizaldi, S. R.·Lee, E. M.·Aceves, J. O.·Murugesh, D. K.·Loots, G. G.·Manilay, J. O.
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Abstract

Natural killer (NK) cells are specialized lymphocytes with the 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 (Sostdc1-/-) 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 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+, mNK) 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-I-deficient cell targets in vitro and in vivo, despite higher CD107a surface levels and similar IFN{gamma} expression to controls. Consistent with Sostdc1s known role in the regulation of Wnt signaling, high levels of Wnt coactivators Tcf7 and Lef1 were observed in Sostdc1-/- NK cells. Expression of the NK development gene Id2 was decreased in Sostdc1-/- iNK and tNK cells, but we observed no changes in Eomes and Tbx21 expression. Reciprocal bone marrow transplant experiments showed that Sostdc1 regulates NK cell maturation and expression of Ly49 receptors in a cell-extrinsic fashion from both non-hematopoietic and hematopoietic sources. 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.\n\nSummary of ResultsO_LISostdc1-/- mice display a partial block between the tNK and mNK developmental stages.\nC_LIO_LISostdc1 influences the Ly49 receptor repertoire on NK cells.\nC_LIO_LINK cells in Sostdc1-/- mice display impaired ability to kill {beta}2m-/- target cells.\nC_LIO_LISostdc1-/- NK cell subsets express high levels of Wnt coactivators Tcf7 and Lef1.\nC_LIO_LIId2 expression is decreased in iNK and tNK cells in the absence of Sostdc1.\nC_LIO_LIBone marrow transplantation experiments demonstrate cell-extrinsic regulation of NK cell maturation by Sostdc1 in both non-hematopoietic (stromal) and hematopoietic cells.\nC_LI

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Millan, A. J., Elizaldi, S. R., Lee, E. M., Aceves, J. O., Murugesh, D. K., Loots, G. G., Manilay, J. O.. 2018-08-09. Sostdc1 regulates natural killer cell maturation and cytotoxicity. https://doi.org/10.1101/387225

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