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

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  • Arunraj Dhamodaran

    (Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
    T-knife Therapeutics, Inc.
    German Cancer Research Center in the Helmholtz Association (DKFZ))

  • 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))

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.

Suggested Citation

  • Arunraj Dhamodaran & Xiaojing Chen & Niklas Fellmer & Deepti Agrawal & Eric Danner & Ralf Kühn & Thomas Blankenstein, 2025. "Mice with a diverse human T cell receptor repertoire selected on multiple HLA class I molecules," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-61306-y
    DOI: 10.1038/s41467-025-61306-y
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