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Atypical sideways recognition of CD1a by autoreactive γδ T cell receptors

Marcin Wegrecki1, Tonatiuh A Ocampo2, Sachith D Gunasinghe1,3

  • 1Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.

Nature Communications
|July 5, 2022
PubMed

Insights

CD1a presents lipids to T cells. This study reveals CD1a also binds Vδ1+ gamma delta T cells (γδ T cells) in a lipid-independent manner, distinct from alpha beta T cell recognition.

Area of Science:

  • Immunology
  • Structural Biology
  • T cell receptor signaling

Background:

  • CD1a is a dendritic cell molecule presenting lipids to alpha beta T cells.
  • The interaction of CD1a with other immune receptors, particularly gamma delta T cells, is not well understood.

Purpose of the Study:

  • To investigate whether CD1a serves as a ligand for gamma delta T cells.
  • To elucidate the structural basis and functional consequences of CD1a recognition by gamma delta T cells.

Main Methods:

  • Utilized CD1a tetramers to identify Vδ1+ γδ T cell interactions with CD1a.
  • Performed functional assays to assess T cell receptor (TCR) binding and signaling.
  • Determined crystal structures of γδ TCR-CD1a-lipid complexes.

Main Results:

  • CD1a is a ligand for Vδ1+ γδ T cells, engaging in lipid-independent binding.
  • Crystal structures reveal a novel 'sideways' binding mode of γδ TCRs to CD1a, distinct from αβ TCR interactions.
  • This autoreactive recognition induces CD1a-specific γδ T cell clustering and proximal signaling via CD3ζ phosphorylation.

Conclusions:

  • Gamma delta T cells recognize CD1a through a unique, antigen-independent mechanism.
  • The distinct binding modality of γδ T cells to CD1a expands our understanding of T cell receptor-antigen interactions.
  • This discovery opens new avenues for exploring γδ T cell functions in immunity and disease.

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