title: Roquin Paralogs Differentially Regulate Functional NKT Cell Subsets.
abstract: NKT cells represent a small subset of glycolipid-recognizing T cells that are heavily implicated in human allergic, autoimmune, and malignant diseases. In the thymus, precursor cells recognize self-glycolipids by virtue of their semi-invariant TCR, which triggers NKT cell lineage commitment and maturation. During their development, NKT cells are polarized into the NKT1, NKT2, and NKT17 subsets, defined through their cytokine-secretion patterns and the expression of key transcription factors. However, we have largely ignored how the differentiation into the NKT cell subsets is regulated. In this article, we describe the mRNA-binding Roquin-1 and -2 proteins as central regulators of murine NKT cell fate decisions. In the thymus, T cell-specific ablation of the Roquin paralogs leads to a dramatic expansion of NKT17 cells, whereas peripheral mature NKT cells are essentially absent. Roquin-1/2-deficient NKT17 cells show exaggerated lineage-specific expression of nearly all NKT17-defining proteins tested. We show through mixed bone marrow chimera experiments that NKT17 polarization is mediated through cell-intrinsic mechanisms early during NKT cell development. In contrast, the loss of peripheral NKT cells is due to cell-extrinsic factors. Surprisingly, Roquin paralog-deficient NKT cells are, in striking contrast to conventional T cells, compromised in their ability to secrete cytokines. Altogether, we show that Roquin paralogs regulate the development and function of NKT cell subsets in the thymus and periphery.
authors.affiliation: III. Medizinische Klinik für Hämatologie und Onkologie, Klinikum Rechts der Isar, Technische Universität München, 81675 Munich, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Drees
authors.affiliation: Molecular Immunology and Signal Transduction Group, Max-Planck Institute of Biochemistry, 82152 Martinsried, Germany; and.
authors.forename: J Christoph
authors.identifier: 0000-0002-1683-8196
authors.initials: JC
authors.lastname: Vahl
authors.affiliation: III. Medizinische Klinik für Hämatologie und Onkologie, Klinikum Rechts der Isar, Technische Universität München, 81675 Munich, Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Bortoluzzi
authors.affiliation: III. Medizinische Klinik für Hämatologie und Onkologie, Klinikum Rechts der Isar, Technische Universität München, 81675 Munich, Germany.|Molecular Immunology and Signal Transduction Group, Max-Planck Institute of Biochemistry, 82152 Martinsried, Germany; and.
authors.forename: Klaus D
authors.initials: KD
authors.lastname: Heger
authors.affiliation: III. Medizinische Klinik für Hämatologie und Onkologie, Klinikum Rechts der Isar, Technische Universität München, 81675 Munich, Germany.
authors.forename: Julius C
authors.identifier: 0000-0002-6951-3416
authors.initials: JC
authors.lastname: Fischer
authors.affiliation: Obesity and Cancer Group, Max-Planck Institute for Metabolism Research, 50931 Cologne, Germany.
authors.forename: F Thomas
authors.initials: FT
authors.lastname: Wunderlich
authors.affiliation: III. Medizinische Klinik für Hämatologie und Onkologie, Klinikum Rechts der Isar, Technische Universität München, 81675 Munich, Germany.
authors.forename: Christian
authors.identifier: 0000-0003-0547-2886
authors.initials: C
authors.lastname: Peschel
authors.affiliation: III. Medizinische Klinik für Hämatologie und Onkologie, Klinikum Rechts der Isar, Technische Universität München, 81675 Munich, Germany; marc.supprian@tum.de.|Molecular Immunology and Signal Transduction Group, Max-Planck Institute of Biochemistry, 82152 Martinsried, Germany; and.
authors.forename: Marc
authors.initials: M
authors.lastname: Schmidt-Supprian
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000276:immunology*; D005434:Flow Cytometry; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D055611:Natural Killer T-Cells / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D044767:Ubiquitin-Protein Ligases / Q000276:immunology*
chemical_list: C501406:Rc3h1 protein, mouse; D044767:Ubiquitin-Protein Ligases