Lightning Talk & Poster Presentation CD1-MR1 Workshop 2025

Lipids presentation in non-classical MHC-I molecules from marsupials (#41)

Tiing Jen Loh 1 , Raghavendra Nagampalli 1 2 , Shuqi Li 3 , Tan-Yun Cheng 3 , Jia Jia Lim 1 , Branch Moody 3 , Jamie Rossjohn 1 4 , Jerome Le Nours 1
  1. Infection and Immunity Program & Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
  2. Department of Immunology, St Jude Children’s Research Hospital, Memphis, TN, 38105, USA
  3. Division of Rheumatology, Immunity and Inflammation, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
  4. Institute of Infection and Immunity, Cardiff University, School of Medicine, Heath Park, Cardiff, CF14 4XN, UK

Objective:

The discovery of a large family of MHC-I-related genes, termed UT, that are only found in non-eutherians (marsupials and monotremes) (1, 2) has spurred research into understanding their function. The UT genes exhibit low polymorphism and homology modelling studies suggested that they may function as MHC-I-like molecules by presenting non-peptide antigens similarly to MR1 and CD1 molecules in humans. However, the overall architecture of the UT molecules as well as their presented ligands are yet to be discovered.

 

Methods:

Using a mammalian expression system, members of the Monodelphis domestica, and Sarcophilus harisii UT family were recombinantly expressed. Using mass spectrometry and X-ray crystallography approaches, the molecular basis of ligand presentation by the UT molecules was established.

Results:

The high-resolution crystal structure of the Monodelphis domestica UT5 and Sarcophilus harisii UT25 revealed the presence of a putative endogenously bound ligand that exhibits the molecular features of a amphipathic lipid.

 

Conclusions:

Our study provides molecular insight into the evolutionary ancestry mammal of an important class of immune receptor and the ligands that can be presented by UT molecules.

 

References:

  1. Papenfuss AT, Feng ZP, Krasnec K, Deakin JE, Baker ML, Miller RD. Marsupials and monotremes possess a novel family of MHC class I genes that is lost from the eutherian lineage. BMC Genomics 16, 535 (2015).

      2. Krasnec KV, Papenfuss AT, Miller RD. The UT family of MHC class I loci unique to non-eutherian mammals has limited polymorphism and tissue specific patterns of expression in the opossum. BMC Immunol 17, 43 (2016).