Lack of Ikaros cripples expression of Foxo1 and its targets in naive T cells.

Publisher: Blackwell Scientific Publications Country of Publication: England NLM ID: 0374672 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1365-2567 (Electronic) Linking ISSN: 00192805 NLM ISO Abbreviation: Immunology Subsets: MEDLINE

Original Publication: Oxford : Blackwell Scientific Publications

CD4-Positive T-Lymphocytes/*metabolism ; Forkhead Box Protein O1/*metabolism ; Ikaros Transcription Factor/*deficiency; Adoptive Transfer ; Animals ; CD4-Positive T-Lymphocytes/drug effects ; CD4-Positive T-Lymphocytes/immunology ; CD4-Positive T-Lymphocytes/transplantation ; Cell Differentiation ; Cell Survival ; Cells, Cultured ; Chemotaxis, Leukocyte ; Forkhead Box Protein O1/genetics ; Forkhead Box Protein O1/immunology ; Gene Expression Regulation ; Genotype ; Ikaros Transcription Factor/genetics ; Ikaros Transcription Factor/immunology ; Interleukin-7/pharmacology ; L-Selectin/genetics ; L-Selectin/immunology ; L-Selectin/metabolism ; Mice, 129 Strain ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Knockout ; Phenotype ; Receptors, Interleukin-17/genetics ; Receptors, Interleukin-17/immunology ; Receptors, Interleukin-17/metabolism ; T-Lymphocytes, Regulatory/immunology ; T-Lymphocytes, Regulatory/metabolism ; Time Factors ; Transcription, Genetic ; Transfection

Ikaros is a transcription factor that regulates lymphocyte development from the level of the haematopoietic stem cell. Lack of Ikaros reduces the ability of progenitor cells to commit to the T-cell lineage, resulting in reduced numbers of early thymic T-cell progenitors and mature T cells. Mature CD4 T cells that lack Ikaros have defects in proliferation, T helper cell differentiation, cytokine expression and the ability to become anergic. A role for Ikaros in the naive T cell has not yet been identified. The receptors interleukin-7 receptor α (IL-7Rα) and l-selectin are important for ensuring survival and proper homing of naive T cells, respectively. Here we show that lack of Ikaros leads to reduced expression of these receptors in naive T cells, which impacts their ability to home and survive in response to IL-7. We define the mechanism underlying this phenotype as a requirement for Ikaros in maintenance of expression of Foxo1, a transcriptional regulator that is required for their expression. We also demonstrate that CD4 T cells lacking Ikaros are significantly crippled in their ability to become induced regulatory T cells, a phenotype also linked to reduced Foxo1 expression. Finally, we show that restoring Ikaros function to Ikaros-deficient CD4 T cells increases levels of Foxo1 message. Together, these studies define, for the first time, a role for Ikaros in naive T cells and establish it as the first transcriptional regulator required for maintaining levels of Foxo1 gene expression in these cells.
(© 2017 John Wiley & Sons Ltd.)

Immunity. 1999 Mar;10(3):333-43. (PMID: 10204489)
Nature. 2012 Nov 22;491(7425):554-9. (PMID: 23135404)
Gene Regul Syst Bio. 2012;6:139-49. (PMID: 23133314)
Eur J Immunol. 2009 Nov;39(11):2991-9. (PMID: 19658095)
Nature. 1983 Jul 7-13;304(5921):30-4. (PMID: 6866086)
J Immunol. 2014 Oct 15;193(8):3934-46. (PMID: 25194055)
Nature. 2006 May 11;441(7090):235-8. (PMID: 16648838)
J Immunol. 2009 Jan 15;182(2):741-5. (PMID: 19124715)
Proc Natl Acad Sci U S A. 2008 Jun 3;105(22):7797-802. (PMID: 18509048)
Immunity. 1999 Mar;10(3):345-55. (PMID: 10204490)
Nat Immunol. 2009 Feb;10 (2):176-84. (PMID: 19136962)
Science. 1992 Oct 30;258(5083):808-12. (PMID: 1439790)
Nat Rev Immunol. 2009 Dec;9(12):823-32. (PMID: 19935802)
Immunity. 2009 Apr 17;30(4):493-507. (PMID: 19345118)
Blood. 2004 Aug 1;104(3):784-7. (PMID: 15069012)
Cell. 1997 Dec 12;91(6):845-54. (PMID: 9413993)
Immunity. 2004 Aug;21(2):289-302. (PMID: 15308108)
Nat Immunol. 2010 Jul;11(7):618-27. (PMID: 20467422)
J Immunol. 1996 Jan 15;156(2):585-92. (PMID: 8543809)
J Immunol. 2007 Dec 1;179(11):7305-15. (PMID: 18025173)
Biochem J. 2004 Jun 1;380(Pt 2):297-309. (PMID: 15005655)
Blood. 2013 Mar 7;121(10):1769-82. (PMID: 23303821)
J Exp Med. 2008 Mar 17;205(3):565-74. (PMID: 18283119)
Immunity. 2010 Dec 14;33(6):890-904. (PMID: 21167754)
Immunity. 1994 Jul;1(4):247-60. (PMID: 7534203)
J Biol Chem. 2013 Dec 6;288(49):35170-9. (PMID: 24145030)
Immunity. 2009 Mar 20;30(3):358-71. (PMID: 19285438)
J Biol Chem. 2011 Sep 2;286(35):30888-97. (PMID: 21730069)
J Exp Med. 1994 Dec 1;180(6):2401-6. (PMID: 7525854)
J Immunol. 1988 Dec 15;141(12):4110-7. (PMID: 3058798)
J Immunol. 2013 Jul 1;191(1):187-99. (PMID: 23733882)
Blood. 2007 Apr 1;109(7):2878-86. (PMID: 17148585)
J Immunol. 2009 Nov 1;183(9):5518-25. (PMID: 19828627)
J Leukoc Biol. 2001 Apr;69(4):675-83. (PMID: 11310856)
Immunity. 2013 Aug 22;39(2):286-97. (PMID: 23932570)
Cell. 1999 Mar 19;96(6):857-68. (PMID: 10102273)
J Biol Chem. 2012 Aug 31;287(36):30436-43. (PMID: 22761423)
Immunity. 1996 Dec;5(6):537-49. (PMID: 8986714)
Trends Mol Med. 2001 May;7(5):213-21. (PMID: 11325633)
Nat Commun. 2015 Oct 13;6:8576. (PMID: 26815406)
J Immunol. 2008 Sep 1;181(5):2980-9. (PMID: 18713968)
Mol Cell Biol. 2005 Mar;25(5):1645-54. (PMID: 15713624)
Cell. 1994 Oct 7;79(1):143-56. (PMID: 7923373)

F30 ES015971 United States ES NIEHS NIH HHS

Keywords: Foxo1; Ikaros; T cell; transcription

0 (Forkhead Box Protein O1)
0 (Foxo1 protein, mouse)
0 (Il17ra protein, mouse)
0 (Interleukin-7)
0 (Receptors, Interleukin-17)
0 (Zfpn1a1 protein, mouse)
126880-86-2 (L-Selectin)
148971-36-2 (Ikaros Transcription Factor)

Date Created: 20170704 Date Completed: 20171017 Latest Revision: 20191210

20250114

PMC5629446

10.1111/imm.12786

28670688