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Title: Sostdc1 Regulates NK Cell Maturation and Cytotoxicity [Sostdc1 regulates natural killer 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 ( 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. Yet, the frequencies of Ly49I +, G2 +, H +, and D + populations were universally decreased at the most mature (CD27 CD11b +) stage. We theorized 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 Tbx21more » 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.« less

Authors:
 [1];  [1]; ORCiD logo [1];  [1];  [1];  [2]; ORCiD logo [1]
  1. Univ. of California Merced, Merced, CA (United States)
  2. Univ. of California Merced, Merced, CA (United States); Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
Publication Date:
Research Org.:
Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
Sponsoring Org.:
USDOE National Nuclear Security Administration (NNSA)
OSTI Identifier:
1527290
Report Number(s):
LLNL-JRNL-755297
Journal ID: ISSN 0022-1767; 942176
Grant/Contract Number:  
AC52-07NA27344
Resource Type:
Accepted Manuscript
Journal Name:
Journal of Immunology
Additional Journal Information:
Journal Volume: 202; Journal Issue: 8; Journal ID: ISSN 0022-1767
Publisher:
The American Association of Immunologists, Inc.
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Millan, Alberto J., Elizaldi, Sonny R., Lee, Eric M., Aceves, Jeffrey O., Murugesh, Deepa, Loots, Gabriela G., and Manilay, Jennifer O. Sostdc1 Regulates NK Cell Maturation and Cytotoxicity [Sostdc1 regulates natural killer cell maturation and cytotoxicity]. United States: N. p., 2019. Web. doi:10.4049/jimmunol.1801157.
Millan, Alberto J., Elizaldi, Sonny R., Lee, Eric M., Aceves, Jeffrey O., Murugesh, Deepa, Loots, Gabriela G., & Manilay, Jennifer O. Sostdc1 Regulates NK Cell Maturation and Cytotoxicity [Sostdc1 regulates natural killer cell maturation and cytotoxicity]. United States. doi:10.4049/jimmunol.1801157.
Millan, Alberto J., Elizaldi, Sonny R., Lee, Eric M., Aceves, Jeffrey O., Murugesh, Deepa, Loots, Gabriela G., and Manilay, Jennifer O. Mon . "Sostdc1 Regulates NK Cell Maturation and Cytotoxicity [Sostdc1 regulates natural killer cell maturation and cytotoxicity]". United States. doi:10.4049/jimmunol.1801157.
@article{osti_1527290,
title = {Sostdc1 Regulates NK Cell Maturation and Cytotoxicity [Sostdc1 regulates natural killer cell maturation and cytotoxicity]},
author = {Millan, Alberto J. and Elizaldi, Sonny R. and Lee, Eric M. and Aceves, Jeffrey O. and Murugesh, Deepa and Loots, Gabriela G. and Manilay, Jennifer O.},
abstractNote = {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. Yet, the frequencies of Ly49I+, G2+, H+, and D+ populations were universally decreased at the most mature (CD27–CD11b+) stage. We theorized 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.},
doi = {10.4049/jimmunol.1801157},
journal = {Journal of Immunology},
number = 8,
volume = 202,
place = {United States},
year = {2019},
month = {4}
}

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