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

Jack L. McMurray, Anouk von Borstel, Taher E. Taher, Eleni Syrimi, Graham S. Taylor, Maria Sharif, Jamie Rossjohn, Ester B.M. Remmerswaal, Frederike J. Bemelman, Felipe A. Vieira Braga, Xi Chen, Sarah A. Teichmann, Fiyaz Mohammed, Andrea A. Berry, Kirsten E. Lyke, Kim C. Williamson, Michael J.T. Stubbington, Martin S. Davey, Carrie R. Willcox, Benjamin E. 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 pages16
JournalCell Reports
Volume39
Issue number8
DOIs
Publication statusPublished - 24 May 2022

Keywords

  • adaptive
  • clonal expansion
  • CP: Immunology
  • CP: Microbiology
  • differentiation
  • effector
  • naive
  • pathogen
  • T cell receptor
  • transcription factor

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