The zinc-finger protein MAZR is part of the transcription factor network that controls the CD4 versus CD8 lineage fate of double-positive thymocytes.
The CD4 versus CD8 lineage specification of thymocytes is linked to coreceptor expression. The transcription factor MAZR has been identified as an important regulator of Cd8 expression. Here we show that variegated CD8 expression by loss of Cd8 enhancers was reverted in MAZR-deficient mice, which confirms that MAZR negatively regulates the Cd8 loci during the transition to the double-positive (DP) stage. Moreover, loss of MAZR led to partial redirection of major histocompatibility complex (MHC) class I-restricted thymocytes into CD4(+) helper-like T cells, which correlated with derepression of Th-POK, a central transcription factor for helper-lineage development. MAZR bound the silencer of the gene encoding Th-POK, which indicated direct regulation of this locus by MAZR. Thus, MAZR is part of the transcription factor network that regulates the CD8 lineage differentiation of DP thymocytes.
Sakaguchi
Shinya
S
Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
Hombauer
Matthias
M
Bilic
Ivan
I
Naoe
Yoshinori
Y
Schebesta
Alexandra
A
Taniuchi
Ichiro
I
Ellmeier
Wilfried
W
D000818:Animals; D016026:Bone Marrow Transplantation; D015704:CD4 Antigens / Q000235:genetics / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D016827:CD8 Antigens / Q000235:genetics / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology; D054338:Cell Transdifferentiation / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D053263:Gene Regulatory Networks; D006183:H-2 Antigens / Q000235:genetics / Q000378:metabolism; D038041:Lymphopoiesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D011828:Radiation Chimera; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D037941:Silencer Elements, Transcriptional / Q000276:immunology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics / Q000276:immunology
D015704:CD4 Antigens; D016827:CD8 Antigens; D006183:H-2 Antigens; D009363:Neoplasm Proteins; D011948:Receptors, Antigen, T-Cell; D012097:Repressor Proteins; D014157:Transcription Factors; C497211:Zbtb7b protein, mouse; C485875:Zfp278 protein, mouse
Nat Immunol. 2008 Oct;9(10):1131-9
18776905
Immunol Cell Biol. 1998 Feb;76(1):34-40
9553774
Nat Immunol. 2006 Apr;7(4):392-400
16491076
Mol Cell Biol. 2000 Mar;20(5):1733-46
10669750
Curr Opin Immunol. 2009 Apr;21(2):127-32
19361971
J Cell Sci. 2002 Feb 15;115(Pt 4):689-98
11865025
Nat Genet. 2001 Nov;29(3):332-6
11687799
Nat Rev Immunol. 2009 Feb;9(2):106-15
19165227
J Pathol. 2008 May;215(1):39-47
18241078
Annu Rev Immunol. 1999;17:523-54
10358767
Trends Cell Biol. 2006 Nov;16(11):578-87
16996269
Nat Rev Immunol. 2002 Dec;2(12):909-19
12461564
Immunity. 2008 Dec 19;29(6):876-87
19062319
Immunity. 2008 Mar;28(3):346-58
18342007
Nature. 2005 Feb 24;433(7028):826-33
15729333
Cell. 1994 Jan 14;76(1):17-27
8287475
Adv Immunol. 2004;83:55-89
15135628
Immunity. 2002 May;16(5):635-47
12049716
J Exp Med. 2008 Jan 21;205(1):245-56
18195075
Nat Rev Immunol. 2008 Oct;8(10):788-801
18802443
Immunity. 2002 May;16(5):623-34
12049715
Nat Immunol. 2005 Apr;6(4):373-81
15750595
J Exp Med. 2007 Aug 6;204(8):1945-57
17646406
Immunol Lett. 2007 Jan 15;108(1):1-9
17084908
Nat Rev Immunol. 2004 Jul;4(7):529-40
15229472
Curr Opin Immunol. 2006 Apr;18(2):135-42
16480861
Nat Immunol. 2001 Dec;2(12):1167-73
11694883
J Immunol. 2005 Feb 1;174(3):1513-24
15661911
Nat Immunol. 2008 Oct;9(10):1122-30
18776904
J Cell Biochem. 2009 Aug 15;107(6):1037-45
19479890
Nat Immunol. 2008 Oct;9(10):1113-21
18776907
Science. 2008 Feb 8;319(5864):822-5
18258917
Cell. 2002 Nov 27;111(5):621-33
12464175
J Exp Med. 2007 Feb 19;204(2):267-72
17296789