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Multi-modal generative modeling for joint analysis of single-cell T cell receptor and gene expression data

Author

Listed:
  • Felix Drost

    (Helmholtz Munich
    Technical University of Munich)

  • Yang An

    (Helmholtz Munich
    Technical University of Munich)

  • Irene Bonafonte-Pardàs

    (Helmholtz Munich)

  • Lisa M. Dratva

    (Wellcome Genome Campus)

  • Rik G. H. Lindeboom

    (The Netherlands Cancer Institute)

  • Muzlifah Haniffa

    (Wellcome Genome Campus
    Newcastle University)

  • Sarah A. Teichmann

    (Wellcome Genome Campus
    University of Cambridge)

  • Fabian Theis

    (Helmholtz Munich
    Technical University of Munich
    Technical University of Munich)

  • Mohammad Lotfollahi

    (Helmholtz Munich
    Wellcome Genome Campus)

  • Benjamin Schubert

    (Helmholtz Munich
    Technical University of Munich)

Abstract

Recent advances in single-cell immune profiling have enabled the simultaneous measurement of transcriptome and T cell receptor (TCR) sequences, offering great potential for studying immune responses at the cellular level. However, integrating these diverse modalities across datasets is challenging due to their unique data characteristics and technical variations. Here, to address this, we develop the multimodal generative model mvTCR to fuse modality-specific information across transcriptome and TCR into a shared representation. Our analysis demonstrates the added value of multimodal over unimodal approaches to capture antigen specificity. Notably, we use mvTCR to distinguish T cell subpopulations binding to SARS-CoV-2 antigens from bystander cells. Furthermore, when combined with reference mapping approaches, mvTCR can map newly generated datasets to extensive T cell references, facilitating knowledge transfer. In summary, we envision mvTCR to enable a scalable analysis of multimodal immune profiling data and advance our understanding of immune responses.

Suggested Citation

  • Felix Drost & Yang An & Irene Bonafonte-Pardàs & Lisa M. Dratva & Rik G. H. Lindeboom & Muzlifah Haniffa & Sarah A. Teichmann & Fabian Theis & Mohammad Lotfollahi & Benjamin Schubert, 2024. "Multi-modal generative modeling for joint analysis of single-cell T cell receptor and gene expression data," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49806-9
    DOI: 10.1038/s41467-024-49806-9
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    References listed on IDEAS

    as
    1. John-William Sidhom & H. Benjamin Larman & Drew M. Pardoll & Alexander S. Baras, 2021. "DeepTCR is a deep learning framework for revealing sequence concepts within T-cell repertoires," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    2. Pradyot Dash & Andrew J. Fiore-Gartland & Tomer Hertz & George C. Wang & Shalini Sharma & Aisha Souquette & Jeremy Chase Crawford & E. Bridie Clemens & Thi H. O. Nguyen & Katherine Kedzierska & Nicole, 2017. "Quantifiable predictive features define epitope-specific T cell receptor repertoires," Nature, Nature, vol. 547(7661), pages 89-93, July.
    3. Yingxia Zheng & Zheyi Chen & Yichao Han & Li Han & Xin Zou & Bingqian Zhou & Rui Hu & Jie Hao & Shihao Bai & Haibo Xiao & Wei Vivian Li & Alex Bueker & Yanhui Ma & Guohua Xie & Junyao Yang & Shiyu Che, 2020. "Immune suppressive landscape in the human esophageal squamous cell carcinoma microenvironment," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
    4. David S. Fischer & Meshal Ansari & Karolin I. Wagner & Sebastian Jarosch & Yiqi Huang & Christoph H. Mayr & Maximilian Strunz & Niklas J. Lang & Elvira D’Ippolito & Monika Hammel & Laura Mateyka & Sim, 2021. "Single-cell RNA sequencing reveals ex vivo signatures of SARS-CoV-2-reactive T cells through ‘reverse phenotyping’," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    5. Justina X. Caushi & Jiajia Zhang & Zhicheng Ji & Ajay Vaghasia & Boyang Zhang & Emily Han-Chung Hsiue & Brian J. Mog & Wenpin Hou & Sune Justesen & Richard Blosser & Ada Tam & Valsamo Anagnostou & Tri, 2021. "Transcriptional programs of neoantigen-specific TIL in anti-PD-1-treated lung cancers," Nature, Nature, vol. 596(7870), pages 126-132, August.
    6. Peter A. Szabo & Hanna Mendes Levitin & Michelle Miron & Mark E. Snyder & Takashi Senda & Jinzhou Yuan & Yim Ling Cheng & Erin C. Bush & Pranay Dogra & Puspa Thapa & Donna L. Farber & Peter A. Sims, 2019. "Single-cell transcriptomics of human T cells reveals tissue and activation signatures in health and disease," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
    7. April R. Kriebel & Joshua D. Welch, 2022. "UINMF performs mosaic integration of single-cell multi-omic datasets using nonnegative matrix factorization," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    8. Justina X. Caushi & Jiajia Zhang & Zhicheng Ji & Ajay Vaghasia & Boyang Zhang & Emily Han-Chung Hsiue & Brian J. Mog & Wenpin Hou & Sune Justesen & Richard Blosser & Ada Tam & Valsamo Anagnostou & Tri, 2021. "Author Correction: Transcriptional programs of neoantigen-specific TIL in anti-PD-1-treated lung cancers," Nature, Nature, vol. 598(7881), pages 1-1, October.
    9. John-William Sidhom & H. Benjamin Larman & Drew M. Pardoll & Alexander S. Baras, 2021. "Author Correction: DeepTCR is a deep learning framework for revealing sequence concepts within T-cell repertoires," Nature Communications, Nature, vol. 12(1), pages 1-1, December.
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