A monoclonal Trd chain supports the development of the complete set of functional γδ T cell lineages

• Published in: Cell reports (Cambridge) Vol. 42; no. 3; p. 112253
• Main Authors: Hahn, Anne M., Vogg, Lisa, Brey, Stefanie, Schneider, Andrea, Schäfer, Simon, Palmisano, Ralph, Pavlova, Anna, Sandrock, Inga, Tan, Likai, Fichtner, Alina S., Prinz, Immo, Ravens, Sarina, Winkler, Thomas H.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 28.03.2023; Elsevier
• Subjects: Animals; Cell Lineage; CP: Immunology; Intraepithelial Lymphocytes; Mice; Mice, Transgenic; Receptors, Antigen, T-Cell, gamma-delta; CP: Immunology
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.112253

The clonal selection theory describes key features of adaptive immune responses of B and T cells. For αβ T cells and B cells, antigen recognition and selection principles are known at a detailed molecular level. The precise role of the antigen receptor in γδ T cells remains less well understood. To better understand the role of the γδ T cell receptor (TCR), we generate an orthotopic TCRδ transgenic mouse model. We demonstrate a multi-layered functionality of γδ TCRs and diverse roles of CDR3δ-mediated selection during γδ T cell development. Whereas epithelial populations using Vγ5 or Vγ7 chains are almost unaffected in their biology in the presence of the transgenic TCRδ chain, pairing with Vγ1 positively selects γδ T cell subpopulations with distinct programs in several organs, thereby distorting the repertoire. In conclusion, our data support dictation of developmental tropism together with adaptive-like recognition principles in a single antigen receptor. [Display omitted] •Orthotopic targeting of the endogenous TCRδ locus with CRISPR-Cas9•The entire functional spectrum of γδ T subsets develops with a monoclonal TCRδ•A Vδ6.2 chain drives thymic positive selection of a Vγ1+ subpopulation•The γδTCR integrates features of innate and adaptive functions To dissect the contribution of antigen receptor specificity during γδ T cell development and function, Hahn et al. generate a mouse model with a monoclonal TCRδ chain that highlights the inter-dependency of γδTCR chains and substantial variation in functional fate acquisition across γδ T cell subsets.