Cholesteryl esters stabilize human CD1c conformations for recognition by self-reactive T cells

Area of Science:

• Immunology
• Structural Biology
• Biochemistry

Background:

• Self-reactive T cells targeting Cluster of Differentiation 1c (CD1c) are common in human blood.
• The specific self-antigens presented by CD1c to these T cells remain largely unidentified.
• Understanding CD1c antigen presentation is crucial for deciphering autoimmune mechanisms.

Purpose of the Study:

• To elucidate the structural basis of CD1c antigen presentation.
• To identify novel ligand classes recognized by CD1c.
• To understand how CD1c conformation influences self-reactive T cell recognition.

Main Methods:

• Determined the crystal structure of CD1c at 2.4 Å resolution.
• Employed computational simulations to explore CD1c conformational changes.
• Utilized binding assays to confirm interactions between CD1c, novel ligands, and T cell receptors.

Main Results:

• Revealed a CD1c crystal structure with an extended antigen-binding groove and a unique conformation.
• Identified cholesteryl esters (CE) and acylated steryl glycosides (ASG) as novel CD1c ligand classes.
• Demonstrated that CE and ASG binding stabilizes CD1c conformations that facilitate self-reactive T cell receptor engagement.

Conclusions:

• Human CD1c adopts distinct conformations based on the occupancy of its antigen-binding groove.
• CE and ASG stabilize CD1c structures that are recognized by self-reactive T cells.
• This conformational plasticity of CD1c is key to its role in presenting self-antigens and potentially driving autoimmune responses.