title: Loss of Roquin induces early death and immune deregulation but not autoimmunity.
abstract: The substitution of one amino acid in the Roquin protein by the sanroque mutation induces a dramatic autoimmune syndrome in mice. This is believed to occur through ectopic expression of inducible T cell co-stimulator (ICOS) and unrestrained differentiation of follicular T helper cells, which induce spontaneous germinal center reactions to self-antigens. In this study, we demonstrate that tissue-specific ablation of Roquin in T or B cells, in the entire hematopoietic system, or in epithelial cells of transplanted thymi did not cause autoimmunity. Loss of Roquin induced elevated expression of ICOS through T cell-intrinsic and -extrinsic mechanisms, which itself was not sufficient to break self-tolerance. Instead, ablation of Roquin in the hematopoietic system caused defined changes in immune homeostasis, including the expansion of macrophages, eosinophils, and T cell subsets, most dramatically CD8 effector-like T cells, through cell-autonomous and nonautonomous mechanisms. Germline Roquin deficiency led to perinatal lethality, which was partially rescued on the genetic background of an outbred strain. However, not even complete absence of Roquin resulted in overt self-reactivity, suggesting that the sanroque mutation induces autoimmunity through an as yet unknown mechanism.
authors.affiliation: Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
authors.forename: Arianna
authors.initials: A
authors.lastname: Bertossi
authors.forename: Martin
authors.initials: M
authors.lastname: Aichinger
authors.forename: Paola
authors.initials: P
authors.lastname: Sansonetti
authors.forename: Maciej
authors.initials: M
authors.lastname: Lech
authors.forename: Frauke
authors.initials: F
authors.lastname: Neff
authors.forename: Martin
authors.initials: M
authors.lastname: Pal
authors.forename: F Thomas
authors.initials: FT
authors.lastname: Wunderlich
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Anders
authors.forename: Ludger
authors.initials: L
authors.lastname: Klein
authors.forename: Marc
authors.initials: M
authors.lastname: Schmidt-Supprian
mesh_terms: D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology / Q000378:metabolism; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D004804:Eosinophils / Q000276:immunology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology*; D018858:Germinal Center / Q000276:immunology / Q000378:metabolism; D007111:Immunity, Cellular; D060889:Inducible T-Cell Co-Stimulator Protein; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; D001324:Autoantigens; C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; C501406:Rc3h1 protein, mouse; D044767:Ubiquitin-Protein Ligases