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Sideways lipid presentation by the antigen-presenting molecule CD1c.

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CD1c presents lipids sideways, not just on top, enabling autoreactive T cell receptor recognition. This dual-presentation mechanism differs from other antigen-presenting molecules.

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Area of Science:

  • Immunology
  • Structural Biology
  • Biochemistry

Background:

  • Antigen recognition by T cell receptors (TCRs) typically involves direct contact with antigen-presenting molecules.
  • The mechanisms by which CD1 molecules present lipid antigens, especially bulky ones, to TCRs are not fully understood.

Purpose of the Study:

  • To investigate how CD1c presents endogenous lipids to autoreactive αβ T cell receptors.
  • To elucidate the structural basis for CD1c-lipid-TCR interactions.

Main Methods:

  • Mass spectrometry analysis of lipids bound to CD1c.
  • Crystal structure determination of CD1c presenting gangliosides.
  • Ex vivo studies of T cell recognition.

Main Results:

  • CD1c binds and presents lipids with bulky headgroups via a novel sideways orientation through a conserved side portal.
  • A general mechanism reveals CD1c simultaneously presenting two lipids (top and side) within its cleft.
  • Sideways-presented gangliosides are recognized by autoreactive T cell receptors.

Conclusions:

  • CD1c employs a unique antigen presentation mechanism, accommodating bulky lipids by presenting them laterally.
  • This sideways presentation allows autoreactive TCRs to recognize CD1c-lipid complexes, expanding the scope of immune recognition.
  • The findings reveal a distinct mode of antigen presentation compared to other antigen-presenting molecules like MHC.