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Sci Immunol. 2019 Feb 8;4(32). pii: eaau6905. doi: 10.1126/sciimmunol.aau6905.
Multifactorial heterogeneity of virus-specific T cells and association with the progression of human chronic hepatitis B infection.
Cheng Y1, Zhu YO2, Becht E1, Aw P2, Chen J1, Poidinger M1, de Sessions PF2, Hibberd ML2,3, Bertoletti A1,4, Lim SG5, Newell EW6,7.
Author information
1
Singapore Immunology Network, Agency for Science, Technology and Research, Singapore.
2
Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore.
3
Emerging Infectious Disease, Department of Pathogen Molecular Biology, London School of Hygiene & Tropical Medicine, London, UK.
4
Emerging Infectious Disease Program, Duke-NUS Medical School, Singapore.
5
Division of Gastroenterology & Hepatology, National University Health System, Singapore.
6
Singapore Immunology Network, Agency for Science, Technology and Research, Singapore. [email protected].
7
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Abstract
Associations between chronic antigen stimulation, T cell dysfunction, and the expression of various inhibitory receptors are well characterized in several mouse and human systems. During chronic hepatitis B virus (HBV) infection (CHB), T cell responses are blunted with low frequencies of virus-specific T cells observed, making these parameters difficult to study. Here, using mass cytometry and a highly multiplexed combinatorial peptide-major histocompatibility complex (pMHC) tetramer strategy that allows for the detection of rare antigen-specific T cells, we simultaneously probed 484 unique HLA-A*1101-restricted epitopes spanning the entire HBV genome on T cells from patients at various stages of CHB. Numerous HBV-specific T cell populations were detected, validated, and profiled. T cells specific for two epitopes (HBVpol387 and HBVcore169) displayed differing and complex heterogeneities that were associated with the disease progression, and the expression of inhibitory receptors on these cells was not linearly related with their extent of T cell dysfunction. For HBVcore169-specific CD8+ T cells, we found cellular markers associated with long-term memory, polyfunctionality, and the presence of several previously unidentified public TCR clones that correlated with viral control. Using high-dimensional trajectory analysis of these cellular phenotypes, a pseudo-time metric was constructed that fit with the status of viral infection in corresponding patients. This was validated in a longitudinal cohort of patients undergoing antiviral therapy. Our study uncovers complex relationships of inhibitory receptors between the profiles of antigen-specific T cells and the status of CHB with implications for new strategies of therapeutic intervention.
Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
PMID:
30737354
DOI:
10.1126/sciimmunol.aau6905
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