Innate TCRβ-chain engagement drives human T cells toward distinct memory-like effector phenotypes with immunotherapeutic potentials

• Published in: Science advances 2023-12, Vol.9 (49), p.eadj6174-eadj6174
• Main Authors: Vantourout, Pierre, Eum, Josephine, Conde Poole, María, Hayday, Thomas S, Laing, Adam G, Hussain, Khiyam, Nuamah, Rosamond, Kannambath, Shichina, Moisan, Jacques, Stoop, Allart, Battaglia, Sebastiano, Servattalab, Roya, Hsu, Jonathan, Bayliffe, Andrew, Katragadda, Madan, Hayday, Adrian C
• Format: Article
• Language: English
• Subjects: Butyrophilins - genetics; Butyrophilins - metabolism; Humans; Immunotherapy; Phenotype; Receptors, Antigen, T-Cell, alpha-beta - genetics; Receptors, Antigen, T-Cell, gamma-delta; T-Lymphocyte Subsets
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/SCIADV.ADJ6174

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.