Activating Receptor Signals Drive Receptor Diversity in Developing Natural Killer Cells.

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101183755 Publication Model: eCollection Cited Medium: Internet ISSN: 1545-7885 (Electronic) Linking ISSN: 15449173 NLM ISO Abbreviation: PLoS Biol Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science, [2003]-

Killer Cells, Natural/*immunology ; NK Cell Lectin-Like Receptor Subfamily A/*immunology ; Receptors, KIR/*immunology ; Signal Transduction/*immunology; Adaptor Proteins, Signal Transducing/genetics ; Adaptor Proteins, Signal Transducing/immunology ; Adaptor Proteins, Signal Transducing/metabolism ; Animals ; Cells, Cultured ; Flow Cytometry ; Genetic Variation/immunology ; Histocompatibility Antigens Class I/immunology ; Histocompatibility Antigens Class I/metabolism ; Humans ; Killer Cells, Natural/metabolism ; Ligands ; Mice, Inbred C57BL ; Mice, Knockout ; NK Cell Lectin-Like Receptor Subfamily A/genetics ; NK Cell Lectin-Like Receptor Subfamily A/metabolism ; Phosphoproteins/genetics ; Phosphoproteins/immunology ; Phosphoproteins/metabolism ; RNA Interference ; Receptors, KIR/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction/genetics

It has recently been appreciated that NK cells exhibit many features reminiscent of adaptive immune cells. Considerable heterogeneity exists with respect to the ligand specificity of individual NK cells and as such, a subset of NK cells can respond, expand, and differentiate into memory-like cells in a ligand-specific manner. MHC I-binding inhibitory receptors, including those belonging to the Ly49 and KIR families, are expressed in a variegated manner, which creates ligand-specific diversity within the NK cell pool. However, how NK cells determine which inhibitory receptors to express on their cell surface during a narrow window of development is largely unknown. In this manuscript, we demonstrate that signals from activating receptors are critical for induction of Ly49 and KIR receptors during NK cell development; activating receptor-derived signals increased the probability of the Ly49 bidirectional Pro1 promoter to transcribe in the forward versus the reverse direction, leading to stable expression of Ly49 receptors in mature NK cells. Our data support a model where the balance of activating and inhibitory receptor signaling in NK cells selects for the induction of appropriate inhibitory receptors during development, which NK cells use to create a diverse pool of ligand-specific NK cells.

Erratum in: PLoS Biol. 2016 Dec 29;14(12):e1002590. doi: 10.1371/journal.pbio.1002590. (PMID: 28033606)

Nat Med. 1999 Apr;5(4):405-11. (PMID: 10202929)
J Immunol. 2000 Aug 1;165(3):1314-21. (PMID: 10903732)
Mol Immunol. 2007 Feb;44(5):821-6. (PMID: 16750269)
J Immunol. 2011 Aug 1;187(3):1212-21. (PMID: 21715685)
J Immunol. 2015 Jun 15;194(12):6068-81. (PMID: 25926675)
J Immunol. 1997 Apr 1;158(7):3174-80. (PMID: 9120271)
Sci Signal. 2012 Jul 10;5(232):ra49. (PMID: 22786724)
Blood. 2009 Mar 12;113(11):2434-41. (PMID: 18974374)
Nucleic Acids Res. 2009 Sep;37(16):5331-42. (PMID: 19605564)
Immunity. 2000 Jul;13(1):143-53. (PMID: 10933402)
J Immunol. 2002 Oct 15;169(8):4253-61. (PMID: 12370356)
J Innate Immun. 2011;3(3):242-8. (PMID: 21411970)
Annu Rev Immunol. 2006;24:257-86. (PMID: 16551250)
J Exp Med. 2004 Oct 18;200(8):1001-13. (PMID: 15477348)
Sci Transl Med. 2013 Oct 23;5(208):208ra145. (PMID: 24154599)
Blood. 2002 Feb 15;99(4):1183-9. (PMID: 11830464)
J Immunol. 1999 Jul 1;163(1):212-6. (PMID: 10384118)
J Immunol. 2002 May 15;168(10):5163-9. (PMID: 11994471)
Eur J Immunol. 2015 Jul;45(7):2072-83. (PMID: 25929249)
PLoS One. 2011 Mar 31;6(3):e18475. (PMID: 21483805)
Eur J Immunol. 1996 Oct;26(10):2286-92. (PMID: 8898935)
J Immunol. 2010 Aug 15;185(4):2009-12. (PMID: 20631304)
J Immunol. 2006 Oct 15;177(8):5177-85. (PMID: 17015703)
PLoS Genet. 2008 Nov;4(11):e1000254. (PMID: 19008943)
Science. 1998 Jul 17;281(5375):416-9. (PMID: 9665885)
J Immunol. 2006 Mar 1;176(5):2991-9. (PMID: 16493057)
Int Immunol. 2008 Mar;20(3):345-52. (PMID: 18203684)
Science. 2001 Sep 21;293(5538):2263-5. (PMID: 11567141)
J Immunol. 2007 Aug 1;179(3):1751-9. (PMID: 17641041)
J Exp Med. 1998 Feb 16;187(4):609-18. (PMID: 9463411)
Immunol Today. 1990 Jul;11(7):237-44. (PMID: 2201309)
Methods Mol Biol. 2010;612:15-26. (PMID: 20033631)
Immunity. 2004 Jul;21(1):55-66. (PMID: 15345220)
Blood. 2009 May 28;113(22):5488-96. (PMID: 19234143)
Eur J Immunol. 1999 Jul;29(7):2223-32. (PMID: 10427985)
Nature. 1986 Feb 20-26;319(6055):675-8. (PMID: 3951539)
J Immunol. 2001 Jun 1;166(11):6585-92. (PMID: 11359811)
J Immunol. 2005 Nov 1;175(9):5966-74. (PMID: 16237090)
Blood. 2013 Apr 18;121(16):3135-46. (PMID: 23407547)
Mol Ther Nucleic Acids. 2014 Sep 02;3:e191. (PMID: 25181276)
Nat Immunol. 2013 Nov;14(11):1127-36. (PMID: 24036998)
J Immunol. 2015 Mar 15;194(6):2847-54. (PMID: 25687756)
PLoS One. 2009 Jun 25;4(6):e6046. (PMID: 19557128)
Mol Immunol. 2005 Feb;42(4):471-5. (PMID: 15607801)
Nat Rev Immunol. 2006 Jan;6(1):67-78. (PMID: 16493428)
Nature. 2009 Jan 29;457(7229):557-61. (PMID: 19136945)
Nat Immunol. 2002 Jun;3(6):523-8. (PMID: 12006976)

T32 AI055428 United States AI NIAID NIH HHS; R21 AI117282 United States AI NIAID NIH HHS; HHSN261200800001C United States CA NCI NIH HHS; R01 HL111501 United States HL NHLBI NIH HHS; R01 HL107589 United States HL NHLBI NIH HHS; HHSN261200800001E United States CA NCI NIH HHS

0 (Adaptor Proteins, Signal Transducing)
0 (Histocompatibility Antigens Class I)
0 (Ligands)
0 (NK Cell Lectin-Like Receptor Subfamily A)
0 (Phosphoproteins)
0 (Receptors, KIR)
0 (SLP-76 signal Transducing adaptor proteins)

Date Created: 20160809 Date Completed: 20170621 Latest Revision: 20240615

20240615

PMC4976927

10.1371/journal.pbio.1002526

27500644