Lightning Talk & Poster Presentation CD1-MR1 Workshop 2025

Advances in the characterisation of antigen presentation by group 1 CD1 antigen-presenting molecules (#15)

Thinh-Phat Cao 1 , Jia Jia Lim 1 , Yanqiong Chen 1 , Guan-Ru Liao 1 , Jamie Rossjohn 1 2 , Adam Shahine 1
  1. Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
  2. Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales, UK

Beyond peptides, various classes of lipids are presented for T cell surveillance via the CD1 family, influencing protective immunity against infection and aberrant autoimmune responses. Until recently, our understanding of antigen presentation by Group 1 CD1 molecules, namely CD1a, CD1b, and CD1c, was significantly lagging behind MHC and Group 2 CD1d, with only a handful of crystal structures solved to guide our understanding of lipid display to T cells. In recent years, our rigorous structural biology program has significantly enhanced our understanding of the various modes of lipid presentation by Group 1 CD1 via new crystal structures and standardised molecular analysis techniques [1]. This aids in defining and reinforcing key molecular features of each CD1 antigen binding pocket that influence lipid capture and display, namely in the impact of allelic variation in human CD1a, providing confirmation of the two-chamber model of lipid capture by CD1b, and more recently, the mechanisms of atypical sideways ganglioside presentation by CD1c. Further, we explore the use of AI-based structural software to computationally predict CD1 antigen binding pocket architecture and modes of lipid docking across vertebrate species, to ascertain whether the molecular features of human CD1 lipid presentation are conserved through evolution. For instance, the four alleles of guinea pig CD1b (gpCD1b), which share a 65-73% sequence identity to human CD1b, are each predicted to vary in overall structure and antigen binding cleft volumes from human CD1b, with gpCD1b allele 3 predicted to form an antigen binding cleft that is over half the volume of human CD1b. Taken together, continually building upon our Group 1 CD1 structural datasets, applying standardised analysis techniques, and the incorporation of new computational tools, all aid in providing a comprehensive understanding of CD1-mediated lipid antigen presentation in immunity.

  1. Huang S, Shahine A, Cheng TY, Chen YL, Ng SW, Balaji GR, Farquhar R, Gras S, Hardman CS, Altman JD, Tahiri N, Minnaard AJ, Ogg GS, Mayfield JA, Rossjohn J, Moody DB. CD1 lipidomes reveal lipid-binding motifs and size-based antigen-display mechanisms. Cell. 2023 Oct 12;186(21):4583-4596.e13. doi: 10.1016/j.cell.2023.08.022. Epub 2023 Sep 18. PMID: 37725977; PMCID: PMC10591967.