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

doi:10.1016/j.celrep.2022.110858

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

Cell Rep. 2022 May 24;39(8):110858. doi: 10.1016/j.celrep.2022.110858.

Authors

Jack L McMurray¹, Anouk von Borstel², Taher E Taher¹, Eleni Syrimi³, Graham S Taylor¹, Maria Sharif¹, Jamie Rossjohn⁴, Ester B M Remmerswaal⁵, Frederike J Bemelman⁶, Felipe A Vieira Braga⁷, Xi Chen⁷, Sarah A Teichmann⁸, Fiyaz Mohammed¹, Andrea A Berry⁹, Kirsten E Lyke⁹, Kim C Williamson¹⁰, Michael J T Stubbington⁷, Martin S Davey¹¹, Carrie R Willcox¹², Benjamin E Willcox¹³

Affiliations

¹ Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK.
² Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.
³ Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK; Department of Haematology, Birmingham Children's Hospital, Birmingham B4 6NH, UK.
⁴ Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK; Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, VIC 3800, Australia.
⁵ Department of Experimental Immunology, Amsterdam Infection and Immunity Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
⁶ Renal Transplant Unit, Division of Internal Medicine, Academic Medical Centre, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
⁷ Wellcome Sanger Institute, Cambridge, UK.
⁸ Wellcome Sanger Institute, Cambridge, UK; European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Cambridge CB10 1SD, UK.
⁹ Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, USA.
¹⁰ Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
¹¹ Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK; Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia. Electronic address: [email protected].
¹² Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK. Electronic address: [email protected].
¹³ Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK. Electronic address: [email protected].

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 B^neg (T_naive) or T-bet⁺Eomes⁺BLIMP-1⁺Granzyme B⁺ (T_effector) transcriptional subtypes, with clonotypically expanded TCRs detected exclusively in T_effector 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 T_naive to T_effector 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.

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

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural

MeSH terms

Adult
CD8-Positive T-Lymphocytes / metabolism
Cell Differentiation
Child, Preschool
Granzymes / metabolism
Humans
Receptors, Antigen, T-Cell, gamma-delta* / metabolism
T-Lymphocyte Subsets* / metabolism

Substances

Receptors, Antigen, T-Cell, gamma-delta
Granzymes

Abstract

Publication types

MeSH terms

Substances

Grants and funding