title: T-box Transcription Factors Combine with the Cytokines TGF-β and IL-15 to Control Tissue-Resident Memory T Cell Fate.
abstract: Tissue-resident memory T (Trm) cells contribute to local immune protection in non-lymphoid tissues such as skin and mucosa, but little is known about their transcriptional regulation. Here we showed that CD8(+)CD103(+) Trm cells, independent of circulating memory T cells, were sufficient for protection against infection and described molecular elements that were crucial for their development in skin and lung. We demonstrated that the T-box transcription factors (TFs) Eomes and T-bet combined to control CD8(+)CD103(+) Trm cell formation, such that their coordinate downregulation was crucial for TGF-β cytokine signaling. TGF-β signaling, in turn, resulted in reciprocal T-box TF downregulation. However, whereas extinguishment of Eomes was necessary for CD8(+)CD103(+) Trm cell development, residual T-bet expression maintained cell surface interleukin-15 (IL-15) receptor β-chain (CD122) expression and thus IL-15 responsiveness. These findings indicate that the T-box TFs control the two cytokines, TGF-β and IL-15, which are pivotal for CD8(+)CD103(+) Trm cell development and survival.
authors.affiliation: Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Parkville, Victoria 3010, Australia. Electronic address: lkmackay@unimelb.edu.au.
authors.forename: Laura K
authors.initials: LK
authors.lastname: Mackay
authors.affiliation: Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Parkville, Victoria 3010, Australia.
authors.forename: Erica
authors.initials: E
authors.lastname: Wynne-Jones
authors.affiliation: Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Parkville, Victoria 3010, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Freestone
authors.affiliation: Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Parkville, Victoria 3010, Australia; Australian Research Council Centre of Excellence for Advanced Molecular Imaging, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Pellicci
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Mielke
authors.affiliation: Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Parkville, Victoria 3010, Australia.
authors.forename: Dane M
authors.initials: DM
authors.lastname: Newman
authors.affiliation: Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Parkville, Victoria 3010, Australia.
authors.forename: Asolina
authors.initials: A
authors.lastname: Braun
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia; Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria 3084, Australia; School of Cancer Medicine, La Trobe University, Melbourne, Victoria 3086, Australia.
authors.forename: Frederick
authors.initials: F
authors.lastname: Masson
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia.
authors.forename: Axel
authors.initials: A
authors.lastname: Kallies
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia.
authors.forename: Gabrielle T
authors.initials: GT
authors.lastname: Belz
authors.affiliation: Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Parkville, Victoria 3010, Australia.
authors.forename: Francis R
authors.initials: FR
authors.lastname: Carbone
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D015536:Down-Regulation; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000276:immunology; D007156:Immunologic Memory / Q000276:immunology*; D019409:Interleukin-15 / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D020825:T-Box Domain Proteins / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000276:immunology*; D000098815:T-bet Transcription Factor
chemical_list: C491198:Eomes protein, mouse; D019409:Interleukin-15; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D016212:Transforming Growth Factor beta
keywords: T-box transcription factors; TGF-β; Tissue-resident memory T cells; peripheral immunity