T-cell-intrinsic Tif1α/Trim24 regulates IL-1R expression on TH2 cells and TH2 cell-mediated airway allergy.
Fiche publication
Date publication
février 2016
Journal
Proceedings of the National Academy of Sciences of the United States of America
Auteurs
Membres identifiés du Cancéropôle Est :
Dr DAVIDSON Irwin
Tous les auteurs :
Perez-Lloret J, Okoye IS, Guidi R, Kannan Y, Coomes SM, Czieso S, Mengus G, Davidson I, Wilson MS
Lien Pubmed
Résumé
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.
Mots clés
Animals, Helminths, immunology, Hypersensitivity, immunology, Mice, Mice, Inbred C57BL, Mice, Transgenic, Nuclear Proteins, genetics, Receptors, Interleukin-1, metabolism, Th2 Cells, immunology, Transcription Factors, genetics
Référence
Proc. Natl. Acad. Sci. U.S.A.. 2016 Feb;113(5):E568-76