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PLoS Pathog. 2019 Apr 18;15(4):e1007715. doi: 10.1371/journal.ppat.1007715. eCollection 2019 Apr.

Distinct phenotype and function of circulating Vδ1+ and Vδ2+ γδT-cells in acute and chronic hepatitis B.

Author information

1
Medical Research, The Corporal Michael J. Crescenz VA Medical Center, Philadelphia PA, United States of America.
2
Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia PA, United States of America.
3
Toronto Centre for Liver Disease, University of Toronto, Toronto, Ontario, Canada.
4
University of Pittsburgh Graduate School of Public Health, Pittsburgh PA, United States of America.
5
Department of Medicine, University of California, San Francisco, San Francisco CA, United States of America.
6
Department of Internal Medicine, Virginia Commonwealth University, Richmond VA, United States of America.
7
Harborview Medical Center, University of Washington Medical Center, Seattle WA, United States of America.
8
Department of Medicine, Beth Israel Deaconess Medical Center, Boston MA, United States of America.
9
Department of Internal Medicine, Mayo Clinic, Rochester MN, United States of America.
10
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas TX, United States of America.
11
Department of Internal Medicine, University of Michigan, Ann Arbor MI, United States of America.

Abstract

Hepatitis B virus (HBV) persists with global and virus-specific T-cell dysfunction, without T-cell based correlates of outcomes. To determine if γδT-cells are altered in HBV infection relative to clinical status, we examined the frequency, phenotype and function of peripheral blood Vδ1+ and Vδ2+γδT-cells by multi-parameter cytometry in a clinically diverse North American cohort of chronic hepatitis B (CHB), acute hepatitis B (AHB) and uninfected control subjects. We show that circulating γδT-cells were comprised predominantly of CD3hiCD4- Vδ2+γδT-cells with frequencies that were 2-3 fold higher among Asian than non-Asian Americans and inversely correlated with age, but without differences between CHB, AHB and control subjects. However, compared to control subjects, CHB was associated with increased TbethiEomesdim phenotype in Vδ2+γδT-cells whereas AHB was associated with increased TbethiEomesdim phenotype in Vδ1+γδT-cells, with significant correlations between Tbet/Eomes expression in γδT-cells with their expression of NK and T-cell activation and regulatory markers. As for effector functions, IFNγ/TNF responses to phosphoantigens or PMA/Ionomycin in Vδ2+γδT-cells were weaker in AHB but preserved in CHB, without significant differences for Vδ1+γδT-cells. Furthermore, early IFNγ/TNF responses in Vδ2+ γδT-cells to brief PMA/Ionomycin stimulation correlated inversely with serum ALT but not HBV DNA. Accordingly, IFNγ/TNF responses in Vδ2+γδT-cells were weaker in patients with CHB with hepatitis flare compared to those without hepatitis flares, and this functional deficit persisted beyond clinical resolution of CHB flare. We conclude that circulating γδT-cells show distinct activation and differentiatiation in acute and chronic HBV infection as part of lymphoid stress surveillance with potential role in clinical outcomes.

Conflict of interest statement

Anna S. F. Lok has received research grants (to the University of Michigan) from Bristol-Myers Squibb and Gilead, and has served on advisory board of Gilead.

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