Hobit and Blimp1 instruct a universal transcriptional program of tissue residency in lymphocytes.
Tissue-resident memory T (Trm) cells permanently localize to portals of pathogen entry, where they provide immediate protection against reinfection. To enforce tissue retention, Trm cells up-regulate CD69 and down-regulate molecules associated with tissue egress; however, a Trm-specific transcriptional regulator has not been identified. Here, we show that the transcription factor Hobit is specifically up-regulated in Trm cells and, together with related Blimp1, mediates the development of Trm cells in skin, gut, liver, and kidney in mice. The Hobit-Blimp1 transcriptional module is also required for other populations of tissue-resident lymphocytes, including natural killer T (NKT) cells and liver-resident NK cells, all of which share a common transcriptional program. Our results identify Hobit and Blimp1 as central regulators of this universal program that instructs tissue retention in diverse tissue-resident lymphocyte populations.
Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, Australia. Australian Research Council (ARC) Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Melbourne, Australia. lkmackay@unimelb.edu.au kallies@wehi.edu.au k.vangisbergen@sanquin.nl.
Laura K
LK
Mackay
Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Vienna, Austria.
Martina
M
Minnich
Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, Netherlands.
Natasja A M
NA
Kragten
The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia. Department of Medical Biology, The University of Melbourne, Melbourne, Australia.
Yang
Y
Liao
Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, AMC, University of Amsterdam, Amsterdam, Netherlands.
Benjamin
B
Nota
The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia. Department of Medical Biology, The University of Melbourne, Melbourne, Australia.
Cyril
C
Seillet
Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, Australia.
Ali
A
Zaid
The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia. Department of Medical Biology, The University of Melbourne, Melbourne, Australia.
Kevin
K
Man
The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia. Department of Medical Biology, The University of Melbourne, Melbourne, Australia.
Simon
S
Preston
Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, Australia.
David
D
Freestone
Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, Australia.
Asolina
A
Braun
Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, Australia.
Erica
E
Wynne-Jones
Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, Netherlands. The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia. Department of Medical Biology, The University of Melbourne, Melbourne, Australia. Department of Experimental Immunology, AMC, Amsterdam, Netherlands.
Felix M
FM
Behr
Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, Netherlands.
Regina
R
Stark
Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, Australia. Australian Research Council (ARC) Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Melbourne, Australia.
Daniel G
DG
Pellicci
Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, Australia. Australian Research Council (ARC) Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Melbourne, Australia.
Dale I
DI
Godfrey
The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia. Department of Medical Biology, The University of Melbourne, Melbourne, Australia.
Gabrielle T
GT
Belz
The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia. Department of Medical Biology, The University of Melbourne, Melbourne, Australia.
Marc
M
Pellegrini
Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, Australia.
Thomas
T
Gebhardt
Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Vienna, Austria.
Meinrad
M
Busslinger
The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia. Department of Computing and Information Systems, The University of Melbourne, Melbourne, Australia.
Wei
W
Shi
Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, Australia.
Francis R
FR
Carbone
Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, Netherlands.
René A W
RA
van Lier
The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia. Department of Medical Biology, The University of Melbourne, Melbourne, Australia. lkmackay@unimelb.edu.au kallies@wehi.edu.au k.vangisbergen@sanquin.nl.
Axel
A
Kallies
Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, Netherlands. The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia. Department of Medical Biology, The University of Melbourne, Melbourne, Australia. Department of Experimental Immunology, AMC, Amsterdam, Netherlands. lkmackay@unimelb.edu.au kallies@wehi.edu.au k.vangisbergen@sanquin.nl.
Klaas P J M
KP
van Gisbergen
D000818:Animals; D041981:Gastrointestinal Tract / Q000276:immunology; D005786:Gene Expression Regulation; D005809:Genes, Regulator / Q000235:genetics / Q000502:physiology*; D007156:Immunologic Memory / Q000235:genetics*; D007668:Kidney / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D008099:Liver / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000276:immunology*; D000074462:Positive Regulatory Domain I-Binding Factor 1; D012867:Skin / Q000276:immunology; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic; D015854:Up-Regulation
C513258:Prdm1 protein, mouse; D014157:Transcription Factors; C000607377:Zfp683 protein, mouse; D000074462:Positive Regulatory Domain I-Binding Factor 1