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<p>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<i>ab</i>-A2 mice which carry human TCRα and TCRβ gene loci and the human leukocyte antigen class I gene HLA-<i>A*02:01</i> and are deficient for the corresponding mouse genes. Into these mice, we here introduce by PiggyBac transposon HLA-<i>A*03:01</i>, -<i>A*11:01</i>, -<i>B*07:02</i>, -<i>B*15:01</i>, -<i>C*04:01</i>, and -<i>C*07:02</i> genes. These mice, termed AB<i>ab</i>-I, exhibit increased peripheral CD8<sup>+</sup> T cell counts and a higher CD8/CD4 ratio compared to AB<i>ab</i>-A2 mice. AB<i>ab</i>-I mice display a broader TCR repertoire with more unique V(D)J-TCRß clonotypes than AB<i>ab</i>-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<i>ab</i>-I mice mount robust immune responses against viral, tumor-associated, and tumor-specific antigens. AB<i>ab</i>-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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月1日

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  • Arunraj Dhamodaran,
  • Xiaojing Chen,
  • Niklas Fellmer,
  • Deepti Agrawal,
  • Eric Danner,
  • Ralf Kühn,
  • Thomas Blankenstein

摘要

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.