Clonally diverse CD38+HLA-DR+CD8+ T cells persist during fatal H7N9 disease

Zhongfang Wang; Lingyan Zhu; Thi H O Nguyen; Yanmin Wan; Sneha Sant; Sergio M Quiñones-Parra; Jeremy Chase Crawford; Auda A Eltahla; Simone Rizzetto; Rowena A Bull; Chenli Qiu; Marios Koutsakos; E Bridie Clemens; Liyen Loh; Tianyue Chen; Lu Liu; Pengxing Cao; Yanqin Ren; Lukasz Kedzierski; Tom Kotsimbos; James M McCaw; Nicole L La Gruta; Stephen J Turner; Allen C Cheng; Fabio Luciani; Xiaoyan Zhang; Peter C Doherty; Paul G Thomas; Jianqing Xu; Katherine Kedzierska

doi:10.1038/s41467-018-03243-7

Clonally diverse CD38⁺HLA-DR⁺CD8⁺ T cells persist during fatal H7N9 disease

Nat Commun. 2018 Feb 26;9(1):824. doi: 10.1038/s41467-018-03243-7.

Authors

Zhongfang Wang^{1

2}, Lingyan Zhu¹, Thi H O Nguyen², Yanmin Wan¹, Sneha Sant², Sergio M Quiñones-Parra², Jeremy Chase Crawford³, Auda A Eltahla⁴, Simone Rizzetto⁴, Rowena A Bull⁴, Chenli Qiu¹, Marios Koutsakos², E Bridie Clemens², Liyen Loh², Tianyue Chen¹, Lu Liu¹, Pengxing Cao⁵, Yanqin Ren¹, Lukasz Kedzierski², Tom Kotsimbos⁶, James M McCaw⁵, Nicole L La Gruta^{2

7}, Stephen J Turner^{2

8}, Allen C Cheng⁹, Fabio Luciani⁴, Xiaoyan Zhang¹, Peter C Doherty^{2

3}, Paul G Thomas³, Jianqing Xu¹⁰, Katherine Kedzierska^{11

12}

Affiliations

¹ Shanghai Public Health Clinical Center & Institutes of Biomedical Sciences, Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, Shanghai Medical College, Fudan University, 201508, Shangai, China.
² Department of Microbiology and Immunology, University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Parkville, Melbourne, VIC, 3010, Australia.
³ Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
⁴ School of Medical Sciences and The Kirby Institute, UNSW Sydney, Sydney, NSW, 2052, Australia.
⁵ School of Mathematics and Statistics, University of Melbourne, Parkville, VIC, 3010, Australia.
⁶ Department of Respiratory Medicine, Alfred Hospital Health and Department Medicine, Monash University, 99 Commercial Road, Melbourne, VIC, 3004, Australia.
⁷ Department of Biochemistry and Molecular Biology, Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia.
⁸ Department of Microbiology, Biomedical Discovery Institute, Monash University, Clayton, VIC, 3800, Australia.
⁹ Infection Prevention and Healthcare Epidemiology Unit, Alfred Health and School of Public Health and Preventive Medicine, 99 Commercial Road, Melbourne, VIC, 3004, Australia.
¹⁰ Shanghai Public Health Clinical Center & Institutes of Biomedical Sciences, Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, Shanghai Medical College, Fudan University, 201508, Shangai, China. [email protected].
¹¹ Shanghai Public Health Clinical Center & Institutes of Biomedical Sciences, Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, Shanghai Medical College, Fudan University, 201508, Shangai, China. [email protected].
¹² Department of Microbiology and Immunology, University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Parkville, Melbourne, VIC, 3010, Australia. [email protected].

Abstract

Severe influenza A virus (IAV) infection is associated with immune dysfunction. Here, we show circulating CD8⁺ T-cell profiles from patients hospitalized with avian H7N9, seasonal IAV, and influenza vaccinees. Patient survival reflects an early, transient prevalence of highly activated CD38⁺HLA-DR⁺PD-1⁺ CD8⁺ T cells, whereas the prolonged persistence of this set is found in ultimately fatal cases. Single-cell T cell receptor (TCR)-αβ analyses of activated CD38⁺HLA-DR⁺CD8⁺ T cells show similar TCRαβ diversity but differential clonal expansion kinetics in surviving and fatal H7N9 patients. Delayed clonal expansion associated with an early dichotomy at a transcriptome level (as detected by single-cell RNAseq) is found in CD38⁺HLA-DR⁺CD8⁺ T cells from patients who succumbed to the disease, suggesting a divergent differentiation pathway of CD38⁺HLA-DR⁺CD8⁺ T cells from the outset during fatal disease. Our study proposes that effective expansion of cross-reactive influenza-specific TCRαβ clonotypes with appropriate transcriptome signatures is needed for early protection against severe influenza disease.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ADP-ribosyl Cyclase 1 / genetics
ADP-ribosyl Cyclase 1 / immunology
CD8-Positive T-Lymphocytes / immunology*
CD8-Positive T-Lymphocytes / pathology
CD8-Positive T-Lymphocytes / virology
Clonal Selection, Antigen-Mediated / genetics*
Cohort Studies
Critical Illness
Gene Expression Regulation
HLA-DR Antigens / genetics
HLA-DR Antigens / immunology
Hospitalization
Humans
Influenza A Virus, H7N9 Subtype / immunology
Influenza A Virus, H7N9 Subtype / pathogenicity*
Influenza, Human / genetics
Influenza, Human / immunology*
Influenza, Human / mortality
Influenza, Human / virology
Lymphocyte Activation
Membrane Glycoproteins / genetics
Membrane Glycoproteins / immunology
Programmed Cell Death 1 Receptor / genetics
Programmed Cell Death 1 Receptor / immunology
Receptors, Antigen, T-Cell, alpha-beta / genetics
Receptors, Antigen, T-Cell, alpha-beta / immunology*
Survival Analysis
T-Lymphocyte Subsets / immunology*
T-Lymphocyte Subsets / pathology
T-Lymphocyte Subsets / virology
Transcriptome / immunology*

Substances

HLA-DR Antigens
Membrane Glycoproteins
PDCD1 protein, human
Programmed Cell Death 1 Receptor
Receptors, Antigen, T-Cell, alpha-beta
CD38 protein, human
ADP-ribosyl Cyclase 1