title: T-cell-intrinsic Tif1α/Trim24 regulates IL-1R expression on TH2 cells and TH2 cell-mediated airway allergy.
abstract: There is a paucity of new therapeutic targets to control allergic reactions and forestall the rising trend of allergic diseases. Although a variety of immune cells contribute to allergy, cytokine-secreting αβ(+)CD4(+) T-helper 2 (TH2) cells orchestrate the type-2-driven immune response in a large proportion of atopic asthmatics. To identify previously unidentified putative targets in pathogenic TH2 cells, we performed in silico analyses of recently published transcriptional data from a wide variety of pathogenic TH cells [Okoye IS, et al. (2014) Proc Natl Acad Sci USA 111(30):E3081-E3090] and identified that transcription intermediary factor 1 regulator-alpha (Tif1α)/tripartite motif-containing 24 (Trim24) was predicted to be active in house dust mite (HDM)- and helminth-elicited Il4(gfp+)αβ(+)CD4(+) TH2 cells but not in TH1, TH17, or Treg cells. Testing this prediction, we restricted Trim24 deficiency to T cells by using a mixed bone marrow chimera system and found that T-cell-intrinsic Trim24 is essential for HDM-mediated airway allergy and antihelminth immunity. Mechanistically, HDM-elicited Trim24(-/-) T cells have reduced expression of many TH2 cytokines and chemokines and were predicted to have compromised IL-1-regulated signaling. Following this prediction, we found that Trim24(-/-) T cells have reduced IL-1 receptor (IL-1R) expression, are refractory to IL-1β-mediated activation in vitro and in vivo, and fail to respond to IL-1β-exacerbated airway allergy. Collectively, these data identify a previously unappreciated Trim24-dependent requirement for IL-1R expression on TH2 cells and an important nonredundant role for T-cell-intrinsic Trim24 in TH2-mediated allergy and antihelminth immunity.
authors.affiliation: Allergy and Anti-Helminth Immunity Laboratory, The Francis Crick Institute, Mill Hill Laboratories, London NW7 1AA, United Kingdom;
authors.forename: Jimena
authors.initials: J
authors.lastname: Perez-Lloret
authors.affiliation: Allergy and Anti-Helminth Immunity Laboratory, The Francis Crick Institute, Mill Hill Laboratories, London NW7 1AA, United Kingdom;
authors.forename: Isobel S
authors.initials: IS
authors.lastname: Okoye
authors.affiliation: Allergy and Anti-Helminth Immunity Laboratory, The Francis Crick Institute, Mill Hill Laboratories, London NW7 1AA, United Kingdom;
authors.forename: Riccardo
authors.initials: R
authors.lastname: Guidi
authors.affiliation: Allergy and Anti-Helminth Immunity Laboratory, The Francis Crick Institute, Mill Hill Laboratories, London NW7 1AA, United Kingdom;
authors.forename: Yashaswini
authors.initials: Y
authors.lastname: Kannan
authors.affiliation: Allergy and Anti-Helminth Immunity Laboratory, The Francis Crick Institute, Mill Hill Laboratories, London NW7 1AA, United Kingdom;
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Coomes
authors.affiliation: Allergy and Anti-Helminth Immunity Laboratory, The Francis Crick Institute, Mill Hill Laboratories, London NW7 1AA, United Kingdom;
authors.forename: Stephanie
authors.initials: S
authors.lastname: Czieso
authors.affiliation: Department of Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67400 Illkirch, France.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Mengus
authors.affiliation: Department of Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67400 Illkirch, France.
authors.forename: Irwin
authors.initials: I
authors.lastname: Davidson
authors.affiliation: Allergy and Anti-Helminth Immunity Laboratory, The Francis Crick Institute, Mill Hill Laboratories, London NW7 1AA, United Kingdom; mark.wilson@crick.ac.uk.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Wilson
mesh_terms: D000818:Animals; D006376:Helminths / Q000276:immunology; D006967:Hypersensitivity / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D017472:Receptors, Interleukin-1 / Q000378:metabolism*; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
chemical_list: D009687:Nuclear Proteins; D017472:Receptors, Interleukin-1; D014157:Transcription Factors; C093517:transcriptional intermediary factor 1
keywords: Th2; Trim24; allergy; asthma; inflammation