A CMV-induced adaptive human Vδ1+ γδ T cell clone recognizes HLA-DR

Area of Science:

• Immunology
• Cellular Biology
• Molecular Genetics

Background:

• The precise roles of gamma delta T cells (γδ T cells) and their T cell receptors (TCRs) in innate and adaptive immunity remain incompletely understood.
• Massive clonal expansion of Vδ1+ γδ T cells during viral infections suggests potential adaptive responses, but their specific ligands are unknown.

Purpose of the Study:

• To determine if the expansion of γδ T cell clones represents antigen-specific, TCR-dependent adaptive immune responses.
• To identify the cognate ligands recognized by a cytomegalovirus (CMV)-induced Vγ3Vδ1+ γδ T cell receptor (TCR).

Main Methods:

• Utilized CRISPR/Cas9-mediated screening to identify genes essential for target cell recognition by a specific γδ TCR.
• Performed further characterization to elucidate the direct interaction between the Vδ1+ TCR and its ligand.

Main Results:

• CRISPR/Cas9 screening identified HLA-DRA, RFXAP, RFX5, and CIITA as critical for target cell recognition by a CMV-induced Vγ3Vδ1+ TCR.
• Subsequent analysis demonstrated a direct interaction between this Vδ1+ TCR and the Major Histocompatibility Complex (MHC) Class II molecule, HLA-DR.
• MHC Class II expression is significantly upregulated by interferon-γ.

Conclusions:

• The identified γδ T cell response is dependent on MHC Class II recognition, indicating a TCR-ligand interaction.
• These findings suggest that γδ T cells can mount an inflammation-induced, MHC-dependent adaptive immune response, particularly during viral infections.