T-box Transcription Factors Combine with the Cytokines TGF-β and IL-15 to Control Tissue-Resident Memory T Cell Fate

Laura K Mackay; Erica Wynne-Jones; David Freestone; Daniel G Pellicci; Lisa A Mielke; Dane M Newman; Asolina Braun; Frederick Masson; Axel Kallies; Gabrielle T Belz; Francis R Carbone

doi:10.1016/j.immuni.2015.11.008

T-box Transcription Factors Combine with the Cytokines TGF-β and IL-15 to Control Tissue-Resident Memory T Cell Fate

Immunity. 2015 Dec 15;43(6):1101-11. doi: 10.1016/j.immuni.2015.11.008.

Authors

Affiliations

¹ 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.
² Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Parkville, Victoria 3010, Australia.
³ 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.
⁴ Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia.
⁵ 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.

PMID: 26682984
DOI: 10.1016/j.immuni.2015.11.008

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.

Keywords: T-box transcription factors; TGF-β; Tissue-resident memory T cells; peripheral immunity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adoptive Transfer
Animals
CD8-Positive T-Lymphocytes / immunology*
Down-Regulation
Flow Cytometry
Gene Expression Regulation / immunology
Immunologic Memory / immunology*
Interleukin-15 / immunology*
Lymphocyte Activation / immunology
Mice
Mice, Knockout
Polymerase Chain Reaction
T-Box Domain Proteins / immunology*
T-Lymphocyte Subsets / immunology
Transforming Growth Factor beta / immunology*

Substances

Eomes protein, mouse
Interleukin-15
T-Box Domain Proteins
T-box transcription factor TBX21
Transforming Growth Factor beta