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<p>Systematic whole-protein screening and comprehensive profiling of antigen-specific CD4<sup>+</sup> T cells are crucial for advancing vaccine design and cancer immunotherapies, yet remain technically challenging. Here, we present a high-throughput platform that utilizes large-scale class II single-chain trimer libraries to detect antigen-specific CD4<sup>+</sup> T cells, while simultaneously profiling their antigen specificity, TCRα/β sequences, MHC restriction, whole transcriptomes, and patient/timepoint origins at single-cell resolution. Upon rigorous platform validation, we screened the full SARS-CoV-2 spike receptor binding domain in a longitudinal cohort of 22 participants, identifying 2,188 antigen-specific CD4<sup>+</sup> T cells and showing key metrics defining the immunogenicity of class II-restricted viral antigens. We further extended the platform to whole-protein screening of HPV-16 E6/E7 in a cohort of precancerous patients, indicating HPV-specific CD4 TCRs that, upon extensive characterization, demonstrate strong therapeutic potential. By integrating high-throughput antigen screening with high-dimensional, multi-modal cellular characterization, our approach provides detailed insight into CD4<sup>+</sup> T cell immunity, potentially guiding vaccine design and next-generation TCR-based cancer immunotherapies.</p>

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Whole-protein screening and multi-modal profiling of antigen-specific CD4+ T cells at single-cell resolution

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月12日

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  • Rongyu Zhang,
  • Jingqi Qi,
  • Michaela McKasson,
  • Jongchan Choi,
  • Vanessa Gutierrez,
  • Conor Brennan,
  • Sunga Hong,
  • William Chour,
  • Rachel H. Ng,
  • Jingyi Xie,
  • Dan Yuan,
  • Andrew Webster,
  • Simranjeet K. Sidhu,
  • Abby Anderson,
  • Daniel Chen,
  • Rick Edmark,
  • Kim M. Murray,
  • Sarah Li,
  • Connor McDonald,
  • Lee Rowen,
  • Shuo Wang,
  • Yusuf Rasheed,
  • Yapeng Su,
  • Jamie R. Wagner,
  • Jia Ming Chen,
  • Karla Nawaly,
  • Jie Fu,
  • Alexandria Duven,
  • Stephen J. Forman,
  • Mihae Song,
  • Saul J. Priceman,
  • Christine E. Brown,
  • Antoni Ribas,
  • Deborah J. Wong,
  • Kelly G. Paulson,
  • Charles W. Drescher,
  • Cristina Puig-Saus,
  • Jason D. Goldman,
  • Cornelia L. Trimble,
  • James R. Heath

摘要

Systematic whole-protein screening and comprehensive profiling of antigen-specific CD4+ T cells are crucial for advancing vaccine design and cancer immunotherapies, yet remain technically challenging. Here, we present a high-throughput platform that utilizes large-scale class II single-chain trimer libraries to detect antigen-specific CD4+ T cells, while simultaneously profiling their antigen specificity, TCRα/β sequences, MHC restriction, whole transcriptomes, and patient/timepoint origins at single-cell resolution. Upon rigorous platform validation, we screened the full SARS-CoV-2 spike receptor binding domain in a longitudinal cohort of 22 participants, identifying 2,188 antigen-specific CD4+ T cells and showing key metrics defining the immunogenicity of class II-restricted viral antigens. We further extended the platform to whole-protein screening of HPV-16 E6/E7 in a cohort of precancerous patients, indicating HPV-specific CD4 TCRs that, upon extensive characterization, demonstrate strong therapeutic potential. By integrating high-throughput antigen screening with high-dimensional, multi-modal cellular characterization, our approach provides detailed insight into CD4+ T cell immunity, potentially guiding vaccine design and next-generation TCR-based cancer immunotherapies.