title: Bcl11b prevents the intrathymic development of innate CD8 T cells in a cell intrinsic manner.
abstract: If Bcl11b activity is compromised, CD4(+)CD8(+) double-positive (DP) thymocytes produce a greatly increased fraction of innate CD8(+) single-positive (SP) cells highly producing IFN-γ, which are also increased in mice deficient of genes such as Itk, Id3 and NF-κB1 that affect TCR signaling. Of interest, the increase in the former two is due to the bystander effect of IL-4 that is secreted by promyelocytic leukemia zinc finger-expressing NKT and γδT cells whereas the increase in the latter is cell intrinsic. Bcl11b zinc-finger proteins play key roles in T cell development and T cell-mediated immune response likely through TCR signaling. We examined thymocytes at and after the DP stage in Bcl11b (F/S826G) CD4cre, Bcl11b (F/+) CD4cre and Bcl11b (+/S826G) mice, carrying the allele that substituted serine for glycine at the position of 826. Here we show that Bcl11b impairment leads to an increase in the population of TCRαβ(high)CD44(high)CD122(high) innate CD8SP thymocytes, together with two different developmental abnormalities: impaired positive and negative selection accompanying a reduction in the number of CD8SP cells, and developmental arrest of NKT cells at multiple steps. The innate CD8SP thymocytes express Eomes and secrete IFN-γ after stimulation with PMA and ionomycin, and in this case their increase is not due to a bystander effect of IL-4 but cell intrinsic. Those results indicate that Bcl11b regulates development of different thymocyte subsets at multiple stages and prevents an excess of innate CD8SP thymocytes.
authors.affiliation: Division of Molecular Biology, Department of Molecular Genetics, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan hirose@med.niigata-u.ac.jp.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hirose
authors.affiliation: Department of Biology, Faculty of Science, Niigata University, Niigata 950-2181, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Touma
authors.affiliation: Division of Molecular Biology, Department of Molecular Genetics, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan.
authors.forename: Rieka
authors.initials: R
authors.lastname: Go
authors.affiliation: Division of Molecular Biology, Department of Molecular Genetics, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Katsuragi
authors.affiliation: Mutagenesis and Genomics Team, RIKEN BioResource Center, Ibaragi 305-0074, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Sakuraba
authors.affiliation: Mutagenesis and Genomics Team, RIKEN BioResource Center, Ibaragi 305-0074, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Gondo
authors.affiliation: Basic Neuroscience Branch, Brain Research Institute, Niigata University, Niigata 951-8510, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Abe
authors.affiliation: Basic Neuroscience Branch, Brain Research Institute, Niigata University, Niigata 951-8510, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Sakimura
authors.affiliation: Division of Molecular Biology, Department of Molecular Genetics, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Mishima
authors.affiliation: Division of Molecular Biology, Department of Molecular Genetics, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Kominami
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology*; D002478:Cells, Cultured; D018960:Hyaluronan Receptors / Q000378:metabolism; D051796:Inhibitor of Differentiation Proteins / Q000235:genetics; D007371:Interferon-gamma / Q000096:biosynthesis; D053646:Interleukin-2 Receptor beta Subunit / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000235:genetics; D055611:Natural Killer T-Cells / Q000276:immunology; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis / Q000276:immunology; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000096:biosynthesis / Q000276:immunology; D012097:Repressor Proteins / Q000235:genetics*; D015398:Signal Transduction / Q000276:immunology; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: C511143:Bcl11b protein, mouse; C476399:Cd44 protein, mouse; D018960:Hyaluronan Receptors; C508022:Il2rb protein, mouse; D051796:Inhibitor of Differentiation Proteins; D053646:Interleukin-2 Receptor beta Subunit; D016328:NF-kappa B; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; C067679:Idb3 protein, mouse; D015847:Interleukin-4; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase
keywords: NKT development; innate-like T cells; thymocyte development