Hobit- and Blimp-1-driven CD4+ tissue-resident memory T cells control chronic intestinal inflammation

Sebastian Zundler; Emily Becker; Marta Spocinska; Monique Slawik; Loreto Parga-Vidal; Regina Stark; Maximilian Wiendl; Raja Atreya; Timo Rath; Moritz Leppkes; Kai Hildner; Rocío López-Posadas; Sören Lukassen; Arif B Ekici; Clemens Neufert; Imke Atreya; Klaas P J M van Gisbergen; Markus F Neurath

doi:10.1038/s41590-018-0298-5

Hobit- and Blimp-1-driven CD4⁺ tissue-resident memory T cells control chronic intestinal inflammation

Nat Immunol. 2019 Mar;20(3):288-300. doi: 10.1038/s41590-018-0298-5. Epub 2019 Jan 28.

Authors

Sebastian Zundler^{1

2}, Emily Becker¹, Marta Spocinska¹, Monique Slawik¹, Loreto Parga-Vidal², Regina Stark², Maximilian Wiendl¹, Raja Atreya¹, Timo Rath¹, Moritz Leppkes¹, Kai Hildner¹, Rocío López-Posadas¹, Sören Lukassen³, Arif B Ekici³, Clemens Neufert¹, Imke Atreya¹, Klaas P J M van Gisbergen^{2

4}, Markus F Neurath⁵

Affiliations

¹ Department of Medicine 1, Kussmaul Campus for Medical Research and Translational Research Center, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany.
² Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, The University of Amsterdam, Amsterdam, Netherlands.
³ Institute of Human Genetics, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany.
⁴ Department of Experimental Immunology, Amsterdam UMC, The University of Amsterdam, Amsterdam, Netherlands.
⁵ Department of Medicine 1, Kussmaul Campus for Medical Research and Translational Research Center, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany. markus.neurath@uk-erlangen.de.

PMID: 30692620
DOI: 10.1038/s41590-018-0298-5

Abstract

Although tissue-resident memory T cells (T_RM cells) have been shown to regulate host protection in infectious disorders, their function in inflammatory bowel disease (IBD) remains to be investigated. Here we characterized T_RM cells in human IBD and in experimental models of intestinal inflammation. Pro-inflammatory T_RM cells accumulated in the mucosa of patients with IBD, and the presence of CD4⁺CD69⁺CD103⁺ T_RM cells was predictive of the development of flares. In vivo, functional impairment of T_RM cells in mice with double knockout of the T_RM-cell-associated transcription factors Hobit and Blimp-1 attenuated disease in several models of colitis, due to impaired cross-talk between the adaptive and innate immune system. Finally, depletion of T_RM cells led to a suppression of colitis activity. Together, our data demonstrate a central role for T_RM cells in the pathogenesis of chronic intestinal inflammation and suggest that these cells could be targets for future therapeutic approaches in IBD.

Publication types

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

MeSH terms

Animals
CD8-Positive T-Lymphocytes / immunology*
CD8-Positive T-Lymphocytes / metabolism
Cells, Cultured
Chronic Disease
Colitis / genetics
Colitis / immunology*
Colitis / metabolism
Cytokines / genetics
Cytokines / immunology
Cytokines / metabolism
Disease Models, Animal
Gene Expression Profiling
Humans
Immunologic Memory / genetics
Immunologic Memory / immunology*
Inflammatory Bowel Diseases / genetics
Inflammatory Bowel Diseases / immunology
Inflammatory Bowel Diseases / metabolism
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Positive Regulatory Domain I-Binding Factor 1 / deficiency
Positive Regulatory Domain I-Binding Factor 1 / genetics
Positive Regulatory Domain I-Binding Factor 1 / immunology*
Transcription Factors / deficiency
Transcription Factors / genetics
Transcription Factors / immunology*

Substances

Cytokines
Prdm1 protein, mouse
Transcription Factors
Zfp683 protein, mouse
Positive Regulatory Domain I-Binding Factor 1