Mice with a diverse human T cell receptor repertoire selected on multiple HLA class I molecules
2025-07-01
T cell receptor (TCR) gene therapy is an effective cancer treatment. Ideally, the TCR should be of human origin and have optimal avidity, e.g., isolated from a tumor antigen-non-tolerant host. Previously, we developed AB ab -A2 mice which carry human TCRα and TCRβ gene loci and the human leukocyte antigen class I gene HLA- A*02:01 and are deficient for the corresponding mouse genes. Into these mice, we here introduce by PiggyBac transposon HLA- A*03:01 , - A*11:01 , - B*07:02 , - B*15:01 , - C*04:01 , and - C*07:02 genes. These mice, termed AB ab -I, exhibit increased peripheral CD8 + T cell counts and a higher CD8/CD4 ratio compared to AB ab -A2 mice. AB ab -I mice display a broader TCR repertoire with more unique V(D)J-TCRß clonotypes than AB ab -A2 mice. Multi-HLA-I expression selected, on average, TCR with longer complementary determining region 3 (CDR3) compared to expression of a single HLA-I. AB ab -I mice mount robust immune responses against viral, tumor-associated, and tumor-specific antigens. AB ab -I mice allow simultaneous epitope and TCR discovery with broad HLA coverage, which could increase the number of cancer patients amenable to TCR-T treatments.