Mice with a diverse human T cell receptor repertoire selected on multiple HLA class I molecules

Arunraj Dhamodaran, Xiaojing Chen, Niklas Fellmer, Deepti Agrawal, Eric Danner, Ralf Kühn and Thomas Blankenstein ()
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Arunraj Dhamodaran: Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
Xiaojing Chen: Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
Niklas Fellmer: T-knife Therapeutics, Inc.
Deepti Agrawal: T-knife Therapeutics, Inc.
Eric Danner: T-knife Therapeutics, Inc.
Ralf Kühn: Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
Thomas Blankenstein: Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract 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 ABab-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 ABab-I, exhibit increased peripheral CD8+ T cell counts and a higher CD8/CD4 ratio compared to ABab-A2 mice. ABab-I mice display a broader TCR repertoire with more unique V(D)J-TCRß clonotypes than ABab-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. ABab-I mice mount robust immune responses against viral, tumor-associated, and tumor-specific antigens. ABab-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.

Date: 2025
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DOI: 10.1038/s41467-025-61306-y

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