Science Bite (3 minute oral presentation with PPT in live session and poster) - Students and ECRs only Lorne Infection and Immunity 2023

Understanding the molecular recognition of Bacteroides fragilis glycosphingolipids by Natural Killer T-cell receptor   (#26)

Praveena Thirunavukkarasu 1 , Sungwhan F. Oh 2 3 , Hee Bum Song 4 , Ji-Sun Yoo 3 , Da-Jung Jung 3 , Deniz Erturk-Hasdemir 2 , Yoon Soo Hwang 4 , Changwon C. Lee 2 , Jérôme Le Nours 1 , Hyunsoo Kim 4 , Jesang Lee 4 , Richard S. Blumberg 5 , Seung Bum Park 4 , Dennis L. Kasper 2 , Jamie Rossjohn 1 6 7
  1. Infection and Immunity program & Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia
  2. Department of Immunology, Blavatnik Institute of Harvard Medical school, Boston, USA
  3. Center for Experimental Therapeutics and Reperfusion injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, USA
  4. CRI center for Chemical Proteomics, Department of Chemistry, Seoul National University, Seoul, Republic of Korea
  5. Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women’s Hospital, Boston, USA
  6. Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Australia, Melbourne, Victoria, Australia
  7. Institute of Infection and Immunity, Cardiff University, Heath Park, Cardiff, UK

The human gut microbiota comprises more than 50% of Bacteroides species that produce small diffusible molecules like sphingolipids that play a key role in modulating the host’s immune responses. In particular, Bacteroides fragilis produces glycosphingolipids similar to α-galactosylceramides termed as ‘BfaGCs’ that can activate type I Natural Killer T (NKT) cells. While they share key chemical similarities with the type I NKT cell marker antigen, α-galactosylceramide (KRN7000), they possess distinctive structural features including short sphinganine chains, branching and functional groups, implying a basis for their unique immunomodulatory properties. Our structural studies on two such CD1d presented BfaGCs in complex with the type I NKT T cell receptor (TCR) revealed that the TCR adopted a parallel docking topology atop the F'-pocket of CD1d in recognising them. Interestingly, the terminal sphinganine branching of the BfaGCs mediated unique interactions within the F'-pocket of CD1d providing a mechanism for their differing agonistic properties. The NKT TCR recognised the CD1d presented stimulatory and non-stimulatory BfaGCs with nanomolar affinities. Thus, BfaGCs were demonstrated to be bonafide CD1d ligands that function as immunomodulatory mediators influencing the host’s defence in the context of NKT cells. Together, this study sheds light on a better understanding of the existing symbiotic relationship between the microbes producing these endogenous lipids and the host.

References:

Sungwhan F. Oh*†, Praveena T*, Hee Bum Song, Ji-Sun Yoo, Da-Jung Jung, Deniz ErturkHasdemir, Yoon Soo Hwang, Changwon C. Lee, Jérôme Le Nours, Hyunsoo Kim, Jesang Lee, Richard S. Blumberg, Jamie Rossjohn†, Seung Bum Park†, and Dennis L. Kasper†. Host immunomodulatory lipids created by symbionts from dietary amino acids. Nature. 2021 Dec;600(7888):302-307.

* Equal first author