Background Interactions between host immune cells and gut microbiota are crucial for the integrity and function of the intestine. How these interactions regulate immune cell responses in the intestine remains a major gap in the field.
Aim We have identified the signalling lymphocyte activation molecule family member 4 (SLAMF4) as an immunomodulator of the intestinal immunity. The aim is to determine how SLAMF4 is acquired in the gut and what its contribution to intestinal immunity is.
Methods Expression of SLAMF4 was assessed in mice and humans. The mechanism of induction was studied using GFPtg bone marrow chimaera mice, lymphotoxin α and TNLG8A-deficient mice, as well as gnotobiotic mice. Role in immune protection was revealed using oral infection with Listeria monocytogenes and Cytobacter rodentium.
Results SLAMF4 is a selective marker of intestinal immune cells of mice and humans. SLAMF4 induction occurs directly in the intestinal mucosa without the involvement of the gut-associated lymphoid tissue. Gut bacterial products, particularly those of gut anaerobes, and gut-resident antigen-presenting cell (APC)TNLG8A are key contributors of SLAMF4 induction in the intestine. Importantly, lack of SLAMF4 expression leads the increased susceptibility of mice to infection by oral pathogens culminating in their premature death.
Conclusions SLAMF4 is a marker of intestinal immune cells which contributes to the protection against enteric pathogens and whose expression is dependent on the presence of the gut microbiota. This discovery provides a possible mechanism for answering the long-standing question of how the intertwining of the host and gut microbial biology regulates immune cell responses in the gut.
- ENTERIC INFECTIONS
- GASTROINTESTINAL IMMUNE RESPONSE
- INTESTINAL BACTERIA
- MUCOSAL IMMUNITY
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AC and DS contributed equally.
Contributors AC, DS, MT, YJ, BC and AL performed the experiments. AL, DS, AC, YS, YL and BC analysed the data. YL provided reagents. AL and YL designed the experiments. AL, DS and AC wrote the manuscript.
Funding NIH (R01AI083642 to YL, The Robert Wood Johnson Foundation_SG (grant # 581534 to AL), The Robert Wood Johnson Foundation (grant # 67038 for the Child Health Institute of NJ).
Competing interests None declared.
Ethics approval The review committee at Rutgers University and the Robert Wood Johnson Medical School.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement We do not have unpublished data from the study. However, as soon as the paper is accepted, we would wish to make our results available to the scientific community. In addition, we would welcome collaboration with others. Our plan includes also presentations at national and international scientific meetings. In addition, important data might be posted on our institutional website and published through our institutional newsletter.
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