Zeb1 represses TCR signaling, promotes the proliferation of T cell progenitors and is essential for NK1.1 ⁺ T cell development.

Publisher: Chinese Society of Immunology;; _b Nature Pub. Group Country of Publication: China NLM ID: 101242872 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2042-0226 (Electronic) Linking ISSN: 16727681 NLM ISO Abbreviation: Cell Mol Immunol Subsets: MEDLINE

Original Publication: Beijing, China : Tokyo, Japan : Chinese Society of Immunology; Nature Pub. Group, 2010-

Receptors, Antigen, T-Cell, alpha-beta*/genetics ; T-Lymphocyte Subsets*; Animals ; Cell Differentiation ; Cell Proliferation ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Signal Transduction/genetics ; Thymus Gland

T cell development proceeds under the influence of a network of transcription factors (TFs). The precise role of Zeb1, a member of this network, remains unclear. Here, we report that Zeb1 expression is induced early during T cell development in CD4 ^- CD8 ^- double-negative (DN) stage 2 (DN2). Zeb1 expression was further increased in the CD4 ⁺ CD8 ⁺ double-positive (DP) stage before decreasing in more mature T cell subsets. We performed an exhaustive characterization of T cells in Cellophane mice that bear Zeb1 hypomorphic mutations. The Zeb1 mutation profoundly affected all thymic subsets, especially DN2 and DP cells. Zeb1 promoted the survival and proliferation of both cell populations in a cell-intrinsic manner. In the periphery of Cellophane mice, the number of conventional T cells was near normal, but invariant NKT cells, NK1.1 ⁺ γδ T cells and Ly49 ⁺ CD8 T cells were virtually absent. This suggested that Zeb1 regulates the development of unconventional T cell types from DP progenitors. A transcriptomic analysis of WT and Cellophane DP cells revealed that Zeb1 regulated the expression of multiple genes involved in the cell cycle and TCR signaling, which possibly occurred in cooperation with Tcf1 and Heb. Indeed, Cellophane DP cells displayed stronger signaling than WT DP cells upon TCR engagement in terms of the calcium response, phosphorylation events, and expression of early genes. Thus, Zeb1 is a key regulator of the cell cycle and TCR signaling during thymic T cell development. We propose that thymocyte selection is perturbed in Zeb1-mutated mice in a way that does not allow the survival of unconventional T cell subsets.
(© 2020. CSI and USTC.)

Proc Natl Acad Sci U S A. 2012 Jul 31;109(31):12286-93. (PMID: 22761313)
Nucleic Acids Res. 2015 Jan;43(Database issue):D447-52. (PMID: 25352553)
Front Immunol. 2014 Apr 02;5:145. (PMID: 24765094)
J Immunol. 2010 Feb 1;184(3):1268-79. (PMID: 20038637)
Clin Cancer Res. 2011 Aug 1;17(15):4936-41. (PMID: 21593194)
Cancer Res. 2018 Jan 1;78(1):30-35. (PMID: 29254997)
Nat Genet. 2015 Dec;47(12):1426-34. (PMID: 26551670)
Nature. 2006 Jul 20;442(7100):299-302. (PMID: 16855590)
J Biol Chem. 1999 Mar 5;274(10):6567-78. (PMID: 10037751)
Cell Mol Life Sci. 2012 Aug;69(15):2527-41. (PMID: 22349261)
Int Immunol. 1999 Oct;11(10):1701-8. (PMID: 10508188)
J Immunol. 2014 May 1;192(9):4017-23. (PMID: 24748636)
Cold Spring Harb Perspect Biol. 2018 May 1;10(5):. (PMID: 28716889)
J Exp Med. 1997 Apr 21;185(8):1467-79. (PMID: 9126927)
Nat Protoc. 2014 Jan;9(1):171-81. (PMID: 24385147)
J Immunol. 2009 Oct 1;183(7):4197-204. (PMID: 19752228)
J Exp Med. 2018 Nov 5;215(11):2887-2900. (PMID: 30287480)
Proc Natl Acad Sci U S A. 2017 Jan 3;114(1):E67-E74. (PMID: 27994150)
J Exp Med. 2009 Jun 8;206(6):1365-78. (PMID: 19451264)
Immunity. 2013 May 23;38(5):984-97. (PMID: 23623381)
J Exp Med. 2011 Jun 6;208(6):1279-89. (PMID: 21606508)
Nat Immunol. 2014 Jan;15(1):80-7. (PMID: 24241693)
Nat Immunol. 2018 Dec;19(12):1366-1378. (PMID: 30420627)
Nat Rev Immunol. 2008 Jan;8(1):9-21. (PMID: 18097446)
J Exp Med. 2015 Nov 16;212(12):2041-56. (PMID: 26503446)
Nat Immunol. 2014 Sep;15(9):815-23. (PMID: 25137456)
Nat Rev Immunol. 2010 Apr;10(4):272-7. (PMID: 20224567)
J Exp Med. 2015 Nov 16;212(12):2015-25. (PMID: 26503444)
J Exp Med. 2015 Nov 16;212(12):2027-39. (PMID: 26503445)
Genome Biol. 2007;8(1):R12. (PMID: 17239257)
Annu Rev Cell Dev Biol. 2016 Oct 6;32:327-348. (PMID: 27712102)
Methods Mol Biol. 2018;1799:121-133. (PMID: 29956149)
Cell. 2019 Feb 7;176(4):897-912.e20. (PMID: 30686579)
Development. 1998 Jan;125(1):21-31. (PMID: 9389660)
J Exp Med. 2018 Apr 2;215(4):1153-1168. (PMID: 29449309)
Nat Rev Immunol. 2012 Sep;12(9):649-61. (PMID: 22918467)
Eur J Immunol. 2010 Aug;40(8):2143-54. (PMID: 20544728)
Mol Immunol. 2009 Mar;46(6):1256-9. (PMID: 19007993)
Immunol Rev. 2016 May;271(1):114-26. (PMID: 27088910)
Eur J Immunol. 2016 Mar;46(3):531-8. (PMID: 26763078)
Cytokine Growth Factor Rev. 2011 Oct-Dec;22(5-6):287-300. (PMID: 22119658)
Nat Immunol. 2010 Mar;11(3):240-9. (PMID: 20154672)
Immunol Rev. 2006 Feb;209:170-5. (PMID: 16448542)
Nat Commun. 2018 Jul 6;9(1):2627. (PMID: 29980684)
Annu Rev Immunol. 2005;23:945-74. (PMID: 15771590)
Immunity. 2005 May;22(5):595-606. (PMID: 15894277)
Nat Immunol. 2008 Oct;9(10):1091-4. (PMID: 18800157)
J Immunol. 2003 Sep 1;171(5):2413-20. (PMID: 12928388)
Immunol Res. 2011 Apr;49(1-3):202-15. (PMID: 21128008)
Mol Cell Biol. 1999 Oct;19(10):7255-63. (PMID: 10490660)
Curr Opin Immunol. 2009 Aug;21(4):391-6. (PMID: 19646850)
Nat Commun. 2019 Apr 3;10(1):1523. (PMID: 30944313)
Nat Commun. 2018 Jul 9;9(1):2650. (PMID: 29985393)
Proc Natl Acad Sci U S A. 2013 Apr 30;110(18):7407-12. (PMID: 23589855)
Trends Immunol. 2019 May;40(5):431-446. (PMID: 30956067)
Nat Immunol. 2005 Nov;6(11):1079-86. (PMID: 16239924)
Nat Immunol. 2015 Nov;16(11):1114-23. (PMID: 26482978)
Eur J Immunol. 2009 Nov;39(11):2991-9. (PMID: 19658095)
Proc Natl Acad Sci U S A. 2014 Jan 7;111(1):E119-28. (PMID: 24344267)
Cancer Discov. 2016 Sep;6(9):986-1005. (PMID: 27422033)

Keywords: T cell selection; TCR signaling; Zeb1; development; transcription

0 (Receptors, Antigen, T-Cell, alpha-beta)

Date Created: 20200514 Date Completed: 20220331 Latest Revision: 20240403

20240403

PMC8429412

10.1038/s41423-020-0459-y

32398809