Poster Presentation The 47th Lorne Conference on Protein Structure and Function 2022

Molecular insights into the recognition of lipid-based antigens by human Type II Natural Killer T cells (#321)

Kean Thai On Chan Yew Poa 1 , Catarina Almeida 2 , Dale Godfrey 2 , Daniel Pellicci 3 , Jamie Rossjohn 1 , Jerome Le Nours 1
  1. Biochemistry & Molecular Biology, Biomedicine Discovery Institute, Monash University, Victoria, Australia
  2. Microbiology & Immunology, University of Melbourne, Melbourne, Victoria, Australia
  3. Murdoch Children’s Research Institute, Parkville, Victoria, Australia

Presently, studies in the field of T cell mediated immunity have mostly focused on understanding the molecular presentation of peptide-derived antigens (Ags) by the Major Histocompatibility Complex (MHC) and their subsequent molecular recognition by the αβ T Cell Receptors (TCR). However, in addition to MHC molecules, it is now clear that there exists other Ag-presenting molecules of the immune system, termed MHC-like, which include the CD1 family of proteins that present lipid-based Ags to specialized subsets of T cells. Here, the Natural Killer T (NKT) cells exist as two major NKT subsets, namely, Type I and Type II NKT cells, and recognize lipid-based antigens that are presented by the MHC-like molecule CD1d (1). Type II NKT cells play critical immunoregulatory roles in diseases such as cancer (2) and multiple sclerosis (3), where host-derived lipid antigens act as potential agonists. Yet, our understanding of human Type II NKT cells, including their role in immunity, is germinal. Key to understanding the biology of human Type II NKT cells is establishing the fundamental principles underpinning Type II NKT TCR recognition determinants.

 

Using CD1d tetramer technology, we identified and characterised Type II NKT cell subsets from the peripheral blood of healthy human donors that exhibited a clear bias towards a Va4 gene usage for the TCRa chain. Here, we determined the first crystal structure of a human Va4+ NKT TCR-CD1d-endogenous lipid ternary complex to atomic resolution. Our structural findings reveal a novel molecular recognition mechanism by a NKT TCR that radically reshape our understanding of NKT-mediated immunity. Ultimately, our discoveries contribute to a better understanding of the role of Type II NKT cells in health and disease (autoimmunity) and may have fundamental relevance in harnessing this arm of the immune system for therapeutic manipulations.

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  3. 3. Jahng A, Maricic I, Aguilera C, Cardell S, Halder RC, Kumar V. Prevention of autoimmunity by targeting a distinct, noninvariant CD1d-reactive T cell population reactive to sulfatide. J Exp Med. 2004;199(7):947-57.