Nonstimulatory peptide–MHC enhances human T-cell antigen-specific responses by amplifying proximal TCR signaling

Xiang Zhao, Shvetha Sankaran, Jiawei Yap, Chien Tei Too, Zi Zong Ho, Garry Dolton, Mateusz Legut, Ee Chee Ren, Andrew K. Sewell, Antonio Bertoletti, Paul A. MacAry, Joanna Brzostek () and Nicholas R. J. Gascoigne ()
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Xiang Zhao: National University of Singapore
Shvetha Sankaran: National University of Singapore
Jiawei Yap: National University of Singapore
Chien Tei Too: National University of Singapore
Zi Zong Ho: Duke-NUS Graduate Medical School
Garry Dolton: University Hospital Wales
Mateusz Legut: University Hospital Wales
Ee Chee Ren: Singapore Immunology Network, A*STAR, 8A Biomedical Grove
Andrew K. Sewell: University Hospital Wales
Antonio Bertoletti: Duke-NUS Graduate Medical School
Paul A. MacAry: National University of Singapore
Joanna Brzostek: National University of Singapore
Nicholas R. J. Gascoigne: National University of Singapore

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: Abstract Foreign antigens are presented by antigen-presenting cells in the presence of abundant endogenous peptides that are nonstimulatory to the T cell. In mouse T cells, endogenous, nonstimulatory peptides have been shown to enhance responses to specific peptide antigens, a phenomenon termed coagonism. However, whether coagonism also occurs in human T cells is unclear, and the molecular mechanism of coagonism is still under debate since CD4 and CD8 coagonism requires different interactions. Here we show that the nonstimulatory, HIV-derived peptide GAG enhances a specific human cytotoxic T lymphocyte response to HBV-derived epitopes presented by HLA-A*02:01. Coagonism in human T cells requires the CD8 coreceptor, but not T-cell receptor (TCR) binding to the nonstimulatory peptide–MHC. Coagonists enhance the phosphorylation and recruitment of several molecules involved in the TCR-proximal signaling pathway, suggesting that coagonists promote T-cell responses to antigenic pMHC by amplifying TCR-proximal signaling.

Date: 2018
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DOI: 10.1038/s41467-018-05288-0

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