Lipid and small-molecule display by CD1 and MR1

Area of Science:

• Immunology
• Molecular Biology
• Structural Biology

Background:

• Antigen-presenting molecules (APMs) like CD1 and MHC class I-related protein (MR1) present non-peptide antigens to T cells.
• The structural basis for T cell receptor (TCR) recognition of CD1-lipid complexes is distinct from MHC-peptide interactions.
• Understanding these interactions is crucial for deciphering adaptive immune responses to microbial lipids and self-antigens.

Purpose of the Study:

• To investigate the structural basis of T cell recognition for CD1 and MR1 antigen-presenting molecules.
• To analyze the human T cell repertoire interacting with CD1 proteins using novel tetramer technology.
• To identify unique T cell receptor (TCR) specificities for CD1b-presented antigens.

Main Methods:

• Utilized tetramers of human CD1a, CD1b, CD1c, and MR1 proteins for T cell analysis.
• Performed detailed analysis of the human T cell repertoire.
• Characterized T cell receptor (TCR) binding footprints on CD1 molecules.

Main Results:

• Demonstrated that CD1 proteins possess laterally asymmetrical antigen-binding platforms, featuring roofs and portals instead of grooves.
• Showed that TCRs can bind CD1 proteins with either left-sided or right-sided footprints, enabling novel antigen recognition modes.
• Identified previously unknown invariant TCRs that bind CD1b molecules, distinct from those associated with natural killer T (NKT) cells and mucosal-associated invariant T (MAIT) cells.

Conclusions:

• The unique structural features of CD1 molecules facilitate diverse T cell recognition pathways.
• Tetramer-based analysis provides powerful tools for dissecting T cell repertoires and identifying novel antigen specificities.
• The discovery of new invariant TCRs binding CD1b expands our understanding of T cell-mediated immunity beyond conventional MHC and known invariant T cell subsets.