tetano
Editor, Senior Moderator
Nat Commun
. 2026 May 12;17(1):3979.
doi: 10.1038/s41467-026-72396-7.
Whole-protein screening and multi-modal profiling of antigen-specific CD4[SUP]+[/SUP] T cells at single-cell resolution
Rongyu Zhang[SUP] 1 2 [/SUP], Jingqi Qi[SUP] 1 2 [/SUP], Michaela McKasson[SUP] 1 [/SUP], Jongchan Choi[SUP] 1 [/SUP], Vanessa Gutierrez[SUP] 1 [/SUP], Conor Brennan[SUP] 1 [/SUP], Sunga Hong[SUP] 1 [/SUP], William Chour[SUP] 1 3 [/SUP], Rachel H Ng[SUP] 1 2 [/SUP], Jingyi Xie[SUP] 1 4 [/SUP], Dan Yuan[SUP] 1 2 [/SUP], Andrew Webster[SUP] 1 [/SUP], Simranjeet K Sidhu[SUP] 1 2 [/SUP], Abby Anderson[SUP] 1 2 [/SUP], Daniel Chen[SUP] 1 [/SUP], Rick Edmark[SUP] 1 [/SUP], Kim M Murray[SUP] 1 [/SUP], Sarah Li[SUP] 1 [/SUP], Connor McDonald[SUP] 1 [/SUP], Lee Rowen[SUP] 1 [/SUP], Shuo Wang[SUP] 1 2 [/SUP], Yusuf Rasheed[SUP] 1 [/SUP], Yapeng Su[SUP] 1 5 [/SUP], Jamie R Wagner[SUP] 6 [/SUP], Jia Ming Chen[SUP] 7 [/SUP], Karla Nawaly[SUP] 7 [/SUP], Jie Fu[SUP] 8 [/SUP], Alexandria Duven[SUP] 9 [/SUP], Stephen J Forman[SUP] 6 [/SUP], Mihae Song[SUP] 10 [/SUP], Saul J Priceman[SUP] 11 [/SUP], Christine E Brown[SUP] 6 [/SUP], Antoni Ribas[SUP] 7 [/SUP], Deborah J Wong[SUP] 7 [/SUP], Kelly G Paulson[SUP] 12 13 [/SUP], Charles W Drescher[SUP] 5 12 [/SUP], Cristina Puig-Saus[SUP] 7 [/SUP], Jason D Goldman[SUP] 9 14 15 [/SUP], Cornelia L Trimble[SUP] 8 [/SUP], James R Heath[SUP] 16 17 18 [/SUP]
Affiliations
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.
. 2026 May 12;17(1):3979.
doi: 10.1038/s41467-026-72396-7.
Whole-protein screening and multi-modal profiling of antigen-specific CD4[SUP]+[/SUP] T cells at single-cell resolution
Rongyu Zhang[SUP] 1 2 [/SUP], Jingqi Qi[SUP] 1 2 [/SUP], Michaela McKasson[SUP] 1 [/SUP], Jongchan Choi[SUP] 1 [/SUP], Vanessa Gutierrez[SUP] 1 [/SUP], Conor Brennan[SUP] 1 [/SUP], Sunga Hong[SUP] 1 [/SUP], William Chour[SUP] 1 3 [/SUP], Rachel H Ng[SUP] 1 2 [/SUP], Jingyi Xie[SUP] 1 4 [/SUP], Dan Yuan[SUP] 1 2 [/SUP], Andrew Webster[SUP] 1 [/SUP], Simranjeet K Sidhu[SUP] 1 2 [/SUP], Abby Anderson[SUP] 1 2 [/SUP], Daniel Chen[SUP] 1 [/SUP], Rick Edmark[SUP] 1 [/SUP], Kim M Murray[SUP] 1 [/SUP], Sarah Li[SUP] 1 [/SUP], Connor McDonald[SUP] 1 [/SUP], Lee Rowen[SUP] 1 [/SUP], Shuo Wang[SUP] 1 2 [/SUP], Yusuf Rasheed[SUP] 1 [/SUP], Yapeng Su[SUP] 1 5 [/SUP], Jamie R Wagner[SUP] 6 [/SUP], Jia Ming Chen[SUP] 7 [/SUP], Karla Nawaly[SUP] 7 [/SUP], Jie Fu[SUP] 8 [/SUP], Alexandria Duven[SUP] 9 [/SUP], Stephen J Forman[SUP] 6 [/SUP], Mihae Song[SUP] 10 [/SUP], Saul J Priceman[SUP] 11 [/SUP], Christine E Brown[SUP] 6 [/SUP], Antoni Ribas[SUP] 7 [/SUP], Deborah J Wong[SUP] 7 [/SUP], Kelly G Paulson[SUP] 12 13 [/SUP], Charles W Drescher[SUP] 5 12 [/SUP], Cristina Puig-Saus[SUP] 7 [/SUP], Jason D Goldman[SUP] 9 14 15 [/SUP], Cornelia L Trimble[SUP] 8 [/SUP], James R Heath[SUP] 16 17 18 [/SUP]
Affiliations
- PMID: 42120368
- DOI: 10.1038/s41467-026-72396-7
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.