Taking a cue from the non-clonotypic activation and positive selection of γδT cells via natural ligands binding to the germline CDR2/HV4 region of the TCRγδ, Vantourout et al. demonstrated that similar targeted antibodies produce highly proliferative αβT cells. Detailed flow, single-cell (RNAseq and CITEseq), and pathway analysis demonstrated that both naive and memory cells were activated and characterized by a unique set of up- and downregulated genes and transcription factors, generating a novel “memory-like effector” (TMLE) state with high effector potential and resident memory characteristics, distinct from cells induced with canonical anti-CD3ε and super antigen-stimulated cells.
Contributed by Ed Fritsch
ABSTRACT: Clonotypic αβ T cell responses to cargoes presented by major histocompatibility complex (MHC), MR1, or CD1 proteins underpin adaptive immunity. Those responses are mostly mediated by complementarity-determining region 3 motifs created by quasi-random T cell receptor (TCR) gene rearrangements, with diversity being highest for TCRγδ. Nonetheless, TCRγδ also displays nonclonotypic innate responsiveness following engagement of germline-encoded Vγ-specific residues by butyrophilin (BTN) or BTN-like (BTNL) proteins that uniquely mediate γδ T cell subset selection. We now report that nonclonotypic TCR engagement likewise induces distinct phenotypes in TCRαβ+ cells. Specifically, antibodies to germline-encoded human TCRVβ motifs consistently activated naïve or memory T cells toward core states distinct from those induced by anti-CD3 or superantigens and from others commonly reported. Those states combined selective proliferation and effector function with activation-induced inhibitory receptors and memory differentiation. Thus, nonclonotypic TCRVβ targeting broadens our perspectives on human T cell response modes and might offer ways to induce clinically beneficial phenotypes in defined T cell subsets.
Author Info: (1) Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King's College London, London, SE1 9RT, UK. Immunosurveillance Laboratory, The Francis Cri
Author Info: (1) Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King's College London, London, SE1 9RT, UK. Immunosurveillance Laboratory, The Francis Crick Institute, London, NW1 1AT, UK. (2) Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King's College London, London, SE1 9RT, UK. Immunosurveillance Laboratory, The Francis Crick Institute, London, NW1 1AT, UK. (3) Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King's College London, London, SE1 9RT, UK. Immunosurveillance Laboratory, The Francis Crick Institute, London, NW1 1AT, UK. (4) Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King's College London, London, SE1 9RT, UK. (5) Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King's College London, London, SE1 9RT, UK. (6) Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King's College London, London, SE1 9RT, UK. Immunosurveillance Laboratory, The Francis Crick Institute, London, NW1 1AT, UK. (7) NIHR BRC Genomics Research Platform, Guy's and St Thomas' NHS Foundation Trust, King's College London School of Medicine, Guy's Hospital, London, SE1 9RT, UK. (8) NIHR BRC Genomics Research Platform, Guy's and St Thomas' NHS Foundation Trust, King's College London School of Medicine, Guy's Hospital, London, SE1 9RT, UK. (9) Marengo Therapeutics, Cambridge, MA 02139, USA. (10) Marengo Therapeutics, Cambridge, MA 02139, USA. (11) Bridge Informatics, Salem, MA, 01970, USA. (12) Marengo Therapeutics, Cambridge, MA 02139, USA. (13) Marengo Therapeutics, Cambridge, MA 02139, USA. (14) Marengo Therapeutics, Cambridge, MA 02139, USA. (15) Marengo Therapeutics, Cambridge, MA 02139, USA. (16) Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King's College London, London, SE1 9RT, UK. Immunosurveillance Laboratory, The Francis Crick Institute, London, NW1 1AT, UK.
