A CMV-induced adaptive human V delta 1(+) gamma delta T cell clone recognizes HLA-DR

Deseke et al. use soluble gamma delta TCRs and CRISPR/Cas9-mediated screening to identify the MHC class II surface receptor HLA-DR as the cognate TCR ligand of a CMV-induced V delta 1(+) gamma delta T cell clone, which is cross-recognizing leukemia cells. The innate and adaptive roles of gamma delta T cells and their clonal gamma delta T cell receptors (TCRs) in immune responses are still unclear. Recent studies of gamma delta TCR repertoire dynamics showed massive expansion of individual V delta 1(+) gamma delta T cell clones during viral infection. To judge whether such expansion is random or actually represents TCR-dependent adaptive immune responses, information about their cognate TCR ligands is required. Here, we used CRISPR/Cas9-mediated screening to identify HLA-DRA, RFXAP, RFX5, and CIITA as required for target cell recognition of a CMV-induced V gamma 3V delta 1(+) TCR, and further characterization revealed a direct interaction of this V delta 1(+) TCR with the MHC II complex HLA-DR. Since MHC II is strongly upregulated by interferon-gamma, these results suggest an inflammation-induced MHC-dependent immune response of gamma delta T cells.