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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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
Issue number8
Publication statusPublished - 24 May 2022

Bibliographical note

Funding Information:
We thank all donors and patients who participated in the study, AMC biobank staff for provision of renal transplant patient samples, and the Anthony Nolan Cell Therapy Centre for cord blood samples. We thank Dr. Matthew McKenzie and the University of Birmingham CMDS Cell Sorting Facility for γδ T cell isolation, the University of Birmingham Protein Expression Facility for use of facilities, FlowCore (Monash University) for cell sorting assistance, and the Medical Genomics facility (MHTP) for their services. We thank US CHMI study volunteers for their contribution and commitment to malaria research; Dr. Gregory Deye, of the National Institutes of Allergy and Infectious Diseases at the National Institutes of Health, for service as program medical officer of the repetitive challenge study at the University of Maryland, Baltimore (UMB); and Faith Pa'ahana-Brown, RN, Lisa Chrisley, RN, Alyson Kwon, Brenda Dorsey, Ana Raquel Da Costa, Jeffrey Crum, Kathleen Strauss, and Biraj Shrestha for their roles in the repetitive challenge study at UMB. We thank Sanaria, Inc. for providing mosquitoes for human malaria infections. The work was supported by Wellcome Trust Investigator award funding, supporting C.R.W. M.S.D. F.M. T.E.T. and M.S. (099266/Z/12/Z and 221725/Z/20/Z to B.E.W.). J.L.McM. was supported by a CRUK non-clinical studentship; F.A.V.B. by Open Targets (; J.R. is supported by an Australian Research Council (ARC) Laureate Fellowship; K.W. and K.E.L. are supported by a National Institutes of Health (NIH), Division of Allergy and Infectious Diseases (NIAID) U01 (AI-110852), distributed by the Henry M. Jackson Foundation (no. 1701447C); and K.E.L. is further supported by additional funding from the NIAID (U01-HD092308, R01-AE141900, and AI110820-06), The Geneva Foundation (V-12VAXHRFS-03), the Medical Technology Enterprise Consortium (MTEC-17-01), and Pfizer (C4591001, site 1002). M.S.D. is supported by an ARC Discovery Early Career Researcher Award (DE200100292), Rebecca L. Cooper Medical Research Foundation Project Grant (PG2020668), and ARC Discovery Project (DP210103327). The opinions and assertions expressed herein are those of the authors and do not necessarily reflect the official policy or position of the Uniformed Services University or the Department of Defense. Conceptualization, B.E.W. C.R.W. and M.S.D.; methodology, C.R.W. M.S.D. J.L.M. T.E.T. and A.v.B.; software, J.L.M.; formal analysis, J.L.M.; investigation, C.R.W. A.v.B. M.S.D. M.S. and T.E.T.; resources, E.S. G.S.T. J.R. E.B.M.R. F.J.B. F.A.V.B. X.C. S.A.T. A.A.B. K.W. K.E.L. and M.J.T.S.; data curation, J.L.M.; writing – original draft, B.E.W. C.R.W. J.L.M. M.S.D. and T.E.T.; writing – review & editing, B.E.W. C.R.W. J.L.M. M.S.D. and A.v.B.; visualization, C.R.W. J.L.M. F.M. M.S.D. A.v.B. and T.E.T.; funding acquisition, B.E.W. and M.S.D. M.J.T.S. has been employed by 10× Genomics since April 2018; this employment had no bearing on this work. The other authors declare no competing financial interests.

Publisher Copyright:
© 2022 The Authors


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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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