Transcriptional profiling of human Vδ1 T cells reveals a pathogen-driven adaptive differentiation program

Jack McMurray, Anouk von Borstel, Taher Taher, Eleni Syrimi, Graham Taylor, Maria Sharif, Jamie Rossjohn, Ester Remmerswaal, Frederike Bemelman, Felipe A Vieira Braga, Xi Chen, Sarah A Teichmann, Fiyaz Mohammed, Andrea Berry, Kirsten Lyke, Kim Williamson, Michael Stubbington, Martin Davey, Carrie Willcox, Benjamin Willcox

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Abstract

γδ T cells are generally considered innate-like lymphocytes, however, an “adaptive-like” γδ compartment has now emerged. To understand transcriptional regulation of adaptive γδ T cell immunobiology, we combined single-cell transcriptomics, T cell receptor (TCR)-clonotype assignment, ATAC-seq, and immunophenotyping. We show that adult Vδ1+ T cells segregate into TCF7+LEF1+Granzyme Bneg (Tnaive) or T-bet+Eomes+BLIMP-1+Granzyme B+ (Teffector) transcriptional subtypes, with clonotypically expanded TCRs detected exclusively in Teffector cells. Transcriptional reprogramming mirrors changes within CD8+ αβ T cells following antigen-specific maturation and involves chromatin remodeling, enhancing cytokine production and cytotoxicity. Consistent with this, in vitro TCR engagement induces comparable BLIMP-1, Eomes, and T-bet expression in naive Vδ1+ and CD8+ T cells. Finally, both human cytomegalovirus and Plasmodium falciparum infection in vivo drive adaptive Vδ1 T cell differentiation from Tnaive to Teffector transcriptional status, alongside clonotypic expansion. Contrastingly, semi-invariant Vγ9+Vδ2+ T cells exhibit a distinct “innate-effector” transcriptional program established by early childhood. In summary, adaptive-like γδ subsets undergo a pathogen-driven differentiation process analogous to conventional CD8+ T cells.
Original languageEnglish
Article number110858
Number of pages22
JournalCell Reports
Volume39
Issue number8
DOIs
Publication statusPublished - 24 May 2022

Keywords

  • adaptive
  • transcription factor
  • naive
  • effector
  • differentiation
  • T cell receptor
  • clonal expansion
  • pathogen

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