This week we profile a recent publication in Science from Dr. Djenet Bousbaine (pictured, left) and the labs of Dr. Hidde Ploegh (center) at Harvard and Dr. Angelina Bilate (right) at the Rockefeller University.
Can you provide a brief overview of your lab’s current research focus?
The intestinal immune system can maintain tolerance to harmless stimuli such as commensal bacteria and food, while providing protective immunity against pathogens. Dysregulation of this balance can trigger overt inflammatory diseases such as inflammatory bowel diseases (IBD), food allergy, or increased susceptibility/reactivity to enteric pathogens. The intestinal epithelium, the single layer that separates the lumen from the underlying tissue, harbors the largest collection of immune cells in the body – the intraepithelial lymphocytes (IELs) – that play crucial roles in maintaining intestinal homeostasis in response to the constant stimulation by the microbiota present in the lumen.
One of the central questions of the Mucida lab is how IELs contribute to the maintenance of intestinal homeostasis and balance between tolerance to harmless antigens and resistance to pathogens. We study the mechanisms by which luminal stimulation induces intestinal immune responses, and the consequences for the host when these mechanisms are disrupted.
The Ploegh lab’s interests are centered on a biochemical dissection of immune responses more generally and on the development of tools to visualize and manipulate these responses. These approaches enabled the antigen discovery work that is an important part for the paper (see 2.)
What is the significance of the findings in this publication?
This work arose from a close collaboration between the Mucida lab at The Rockefeller University and the Ploegh lab at Harvard.
Bousbaine et al., showed that a conserved enzyme (β-hexosaminidase, β-hex) expressed by intestinal commensal bacteria contributes to the development of anti-inflammatory intestinal T cells. This antigen is conserved across a wide range of Bacteroidetes species, one of the most abundant phyla of bacteria found in the human intestine. β-hex specific T lymphocytes partially protected mice from colitis even in the absence of regulatory T cells. This work shows that an antigen shared by abundant commensal bacteria can generate an anti-inflammatory response at the intestinal mucosa. These findings could have important implications for the understanding of how immune responses against innocuous commensal bacteria can help prevent inflammatory diseases such as IBD. Immunity elicited against specific bacterial species, for example by vaccination, could therefore represent an important non-invasive approach for intestinal inflammatory diseases.
What are the next steps for this research?
Among the many intestinal lymphocyte subsets, CD4 T lymphocytes finely tune responses at the level of antigen recognition and functional differentiation. In the intestinal epithelium and underlying lamina propria, these CD4 T cells can adopt a pro-inflammatory or regulatory phenotype and coordinate immunity and tolerance to diverse intestinal stimuli. We use genetic fate-mapping and gnotobiotic mouse models to study how antigen diversity derived from microbiota can affect fate and functional outcome of intestinal CD4 T cells, and how the different types of immune responses can each contribute to the maintenance of intestinal homeostasis.
If you’d like to mention your funding sources, please list them.
We would like to thank our funding agencies: MIT Center for Microbiome Informatics & Therapeutics (CMIT), FASI/FARE, the National Institute of Health (NIH), MGH ECOR and the Swiss National Science Foundation.
