Nat Immunol. 2021 Dec;22(12):1590-1598. doi: 10.1038/s41590-021-01073-2. | PubMed

Ke-Yue Ma¹, Alexandra A Schonnesen², Chenfeng He², Amanda Y Xia³, Eric Sun², Eunise Chen⁴, Katherine R Sebastian⁵, Yu-Wan Guo^6,7, Robert Balderas⁸, Mrinalini Kulkarni-Date⁵, Ning Jiang^{9,10,11,12,13}

1. Interdisciplinary Life Sciences Graduate Programs, The University of Texas at Austin, Austin, TX, USA.
2. Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, USA.
3. Department of Molecular Biosciences, The University of Texas atAustin, Austin, TX, USA.
4. Department of Nutritional Sciences, The University of Texas at Austin, Austin, TX, USA.
5. Department of Internal Medicine, Dell Medical School, The University of Texas at Austin, Austin, TX, USA.
6. McKetta Department of Chemical Engineering, The University of Texas at Austin, Austin, TX, USA.
7. Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA.
8. Becton Dickinson, San Jose, CA, USA.
9. Interdisciplinary Life Sciences Graduate Programs, The University of Texas at Austin, Austin, TX, USA. jnjiang@upenn.edu.
10. Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, USA. jnjiang@upenn.edu.
11. Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA. jnjiang@upenn.edu.
12. Department of Oncology, Dell Medical School, The University of Texas at Austin, Austin, TX, USA. jnjiang@upenn.edu.
13. Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. jnjiang@upenn.edu.

Abstract

Although critical to T cell function, antigen specificity is often omitted in high-throughput multiomics-based T cell profiling due to technical challenges. We describe a high-dimensional, tetramer-associated T cell antigen receptor (TCR) sequencing (TetTCR-SeqHD) method to simultaneously profile cognate antigen specificities, TCR sequences, targeted gene expression and surface-protein expression from tens of thousands of single cells. Using human polyclonal CD8+ T cells with known antigen specificity and TCR sequences, we demonstrate over 98% precision for detecting the correct antigen specificity. We also evaluate gene expression and phenotypic differences among antigen-specific CD8+ T cells and characterize phenotype signatures of influenza- and Epstein-Barr virus-specific CD8+ T cells that are unique to their pathogen targets. Moreover, with the high-throughput capacity of profiling hundreds of antigens simultaneously, we apply TetTCR-SeqHD to identify antigens that preferentially enrich cognate CD8+ T cells in patients with type 1 diabetes compared to healthy controls and discover a TCR that cross-reacts with diabetes-related and microbiome antigens. TetTCR-SeqHD is a powerful approach for profiling T cell responses in humans and mice.

Presented By Yu-Wan Guo