Interferon-epsilon is a novel regulator of NK cell responses in the uterus

Jemma R Mayall; Jay C Horvat; Niamh E Mangan; Anne Chevalier; Huw McCarthy; Daniel Hampsey; Chantal Donovan; Alexandra C Brown; Antony Y Matthews; Nicole A de Weerd; Eveline D de Geus; Malcolm R Starkey; Richard Y Kim; Katie Daly; Bridie J Goggins; Simon Keely; Steven Maltby; Rennay Baldwin; Paul S Foster; Michael J Boyle; Pradeep S Tanwar; Nicholas D Huntington; Paul J Hertzog; Philip M Hansbro

doi:10.1038/s44321-023-00018-6

Interferon-epsilon is a novel regulator of NK cell responses in the uterus

EMBO Mol Med. 2024 Feb;16(2):267-293. doi: 10.1038/s44321-023-00018-6. Epub 2024 Jan 23.

Authors

Jemma R Mayall^#¹, Jay C Horvat^#¹, Niamh E Mangan², Anne Chevalier¹, Huw McCarthy¹, Daniel Hampsey¹, Chantal Donovan³, Alexandra C Brown¹, Antony Y Matthews², Nicole A de Weerd², Eveline D de Geus², Malcolm R Starkey^{1

4}, Richard Y Kim^{1

3}, Katie Daly¹, Bridie J Goggins¹, Simon Keely¹, Steven Maltby¹, Rennay Baldwin¹, Paul S Foster¹, Michael J Boyle^{1

5}, Pradeep S Tanwar⁶, Nicholas D Huntington⁷, Paul J Hertzog^#², Philip M Hansbro^#^{8

9}

Affiliations

¹ Immune Health Program, Hunter Medical Research Institute and the University of Newcastle, Newcastle, NSW, 2308, Australia.
² Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research and Departments of Molecular and Translational Sciences, Monash University, Clayton, VIC, 3168, Australia.
³ Centre for Inflammation, Centenary Institute and University of Technology Sydney, Faculty of Science, School of Life Sciences, Sydney, NSW, 2000, Australia.
⁴ Immunology and Pathology, Central Clinical School, Monash University, Clayton, VIC, 3168, Australia.
⁵ Immunology and Infectious Diseases Unit, John Hunter Hospital, Newcastle, NSW, 2305, Australia.
⁶ Gynecology Oncology Research Group, School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, NSW, 2308, Australia.
⁷ Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3168, Australia.
⁸ Immune Health Program, Hunter Medical Research Institute and the University of Newcastle, Newcastle, NSW, 2308, Australia. philip.hansbro@uts.edu.au.
⁹ Centre for Inflammation, Centenary Institute and University of Technology Sydney, Faculty of Science, School of Life Sciences, Sydney, NSW, 2000, Australia. philip.hansbro@uts.edu.au.

^# Contributed equally.

Abstract

The uterus is a unique mucosal site where immune responses are balanced to be permissive of a fetus, yet protective against infections. Regulation of natural killer (NK) cell responses in the uterus during infection is critical, yet no studies have identified uterine-specific factors that control NK cell responses in this immune-privileged site. We show that the constitutive expression of IFNε in the uterus plays a crucial role in promoting the accumulation, activation, and IFNγ production of NK cells in uterine tissue during Chlamydia infection. Uterine epithelial IFNε primes NK cell responses indirectly by increasing IL-15 production by local immune cells and directly by promoting the accumulation of a pre-pro-like NK cell progenitor population and activation of NK cells in the uterus. These findings demonstrate the unique features of this uterine-specific type I IFN and the mechanisms that underpin its major role in orchestrating innate immune cell protection against uterine infection.

Keywords: Chlamydia Infection; Female Reproductive Tract; Interferon-Epsilon; Natural Killer Cell; Type I Interferon.

MeSH terms

Female
Fetus
Humans
Interferons
Killer Cells, Natural*
Uterus*

Substances

Interferons

Abstract

MeSH terms

Substances

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