Humanization of T cell-mediated immunity in mice

• Published in: Science immunology Vol. 6; no. 66; p. eabj4026
• Main Authors: Moore, Michael J, Zhong, Maggie, Hansen, Johanna, Gartner, Hans, Grant, Craig, Huang, Mei, Harris, Faith M, Tu, Naxin, Bowerman, Natalie A, Edelmann, Kurt H, Barry, Thomas, Herbin, Olivier, Tay, Chin-Siean, DiLillo, David J, Decker, Corinne E, Levenkova, Natasha, Shevchuk, James, Dhanik, Ankur, Meagher, Karoline A, Karr, Amanda, Roos, Jan, Lee, Wen-Yi, Suh, David, Eckersdorff, Mark, Meagher, T Craig, Koss, Matthew, Esau, Lakeisha, Sleeman, Matthew A, Babb, Robert, Chen, Gang, Kyratsous, Christos A, Poueymirou, William T, McWhirter, John R, Voronina, Vera A, Guo, Chunguang, Gurer, Cagan, Yancopoulos, George D, Murphy, Andrew J, Macdonald, Lynn E
• Format: Journal Article
• Language: English
• Published: United States 24.12.2021
• Subjects: Animals; Humans; Mice; Mice, Inbred C57BL; Receptors, Antigen, T-Cell, alpha-beta - genetics; Receptors, Antigen, T-Cell, alpha-beta - immunology; T-Lymphocytes - immunology
• ISSN: 2470-9468
• DOI: 10.1126/sciimmunol.abj4026

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.