Using VelociGene technology, Moore, Zhong, and Hansen et al. replaced murine TCRαβ variable regions, and CD4, CD8, MHC-I, and MHC-II ectodomain-encoding regions with corresponding human sequences to engineer genetically humanized T cell immunity in mice (VelociT). VelociT mice showed normal lymphoid and myeloid populations, proper expression and regulation of MHC loci, and diverse TCR repertoires; they also developed experimental autoimmune encephalomyelitis. VelociT mice elicited robust T cell responses to LCMV and TAA challenges, and facilitated isolation of potent antitumor TCRs against human antigens.
Contributed by Shishir Pant
ABSTRACT: Despite the enormous promise of T cell therapies, the isolation and study of human T cell receptors (TCRs) of dedicated specificity remains a major challenge. To overcome this limitation, we generated mice with a genetically humanized system of T cell immunity. We used VelociGene technology to replace the murine TCRαβ variable regions, along with regions encoding the extracellular domains of co-receptors CD4 and CD8, and major histocompatibility complex (MHC) class I and II, with corresponding human sequences. The resulting “VelociT” mice have normal myeloid and lymphoid immune cell populations, including thymic and peripheral αβ T cell subsets comparable with wild-type mice. VelociT mice expressed a diverse TCR repertoire, mounted functional T cell responses to lymphocytic choriomeningitis virus infection, and could develop experimental autoimmune encephalomyelitis. Immunization of VelociT mice with human tumor-associated peptide antigens generated robust, antigen-specific responses and led to identification of a TCR against tumor antigen New York esophageal squamous cell carcinoma-1 with potent antitumor activity. These studies demonstrate that VelociT mice mount clinically relevant T cell responses to both MHC-I– and MHC-II–restricted antigens, providing a powerful new model for analyzing T cell function in human disease. Moreover, VelociT mice are a new platform for de novo discovery of therapeutic human TCRs.