Oral Presentation 14th Lorne Infection and Immunity 2024

Understanding T cell-mediated immunity of Bacteroides fragilis glycosphingolipids by Natural Killer T cell receptor   (#10)

Praveena Thirunavukkarasu 1 , Sungwhan F.Oh 2 3 , Heebum 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 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. Institute of Infection and Immunity, Cardiff University, Heath Park, Cardiff, UK
  7. Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Australia, Melbourne, Victoria, Australia

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. The co-culture assay performed with bone marrow-derived dendritic cells and NKT cells in the presence of specific BfaGCs indicated that branching in their sphinganine chain is a critical determinant of NKT cell activation. As such, the strong stimulators measured by their IL-2 release were the compounds that contained the branched sphinganine chains. Our structural studies on two such CD1d-presented BfaGCs in complex with the type I NKT TCR revealed the TCR adopted a parallel docking topology atop the F’-pocket of CD1d in recognising the presented BfaGCs. 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 highlights the structural and molecular-level paradigm of existing symbiotic relationship between the microbes producing these endogenous lipids and the host.

 

References: (* Equal first author)

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.