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Natural Killer Cells Induce CD8⁺ T Cell Dysfunction via Galectin-9/TIM-3 in Chronic Hepatitis B Virus Infection.

ABSTRACT: The antiviral response of natural killer (NK) cells and CD8⁺ T cells is weak in patients with chronic hepatitis B (CHB) infection. However, the specific characteristics of these cells and the association between NK cells and CD8⁺ T cell dysfunction is not well known. In this study, higher galectin-9 (Gal-9) expression was observed in circulating NK cells from CHB patients than from healthy controls and was found to contribute to NK cell dysfunction. In addition, circulating CD8⁺ T cells showed obvious dysfunction and overexpressed TIM-3, the natural receptor of Gal-9, during active CHB infection. Gal-9⁺ and Gal-9^- NK cells from active CHB patients were sorted and cocultured with autologous CD8⁺ T cells. The proportion of tetramer⁺CD8⁺ T cells and the cytokines production of CD8⁺ T cells were lower after cocultivation with Gal-9⁺ than with Gal-9^- NK cells. We showed that in vitro depletion of NK cells increased circulating hepatitis B virus (HBV)-specific CD8⁺ T cell responses in patients with active CHB infection. Because Gal-9 is increased in the serum of CHB patients, CD8⁺ T cells were sorted and cultured with exogenous Gal-9, resulting in lower IFN-γ, TNF-α, CD107a, and granzyme B levels, decreased expression of the activation receptor CD69, increased expression of TIM-3, and a high percentage of early apoptotic CD8⁺ T cells. Blocking Gal-9 or TIM-3 in vitro in a culture of peripheral blood mononuclear cells (PBMCs) stimulated with HBV peptide from active CHB patients restored CD8⁺ T cell function. However, blocking Gal-9 in vitro after removal of NK cells from PBMCs did not rescue CD8⁺ T cells exhaustion. Furthermore, NK and CD8⁺ T cells from active CHB patients were sorted and cocultured in vitro, and the exhaustion of CD8⁺ T cells were alleviated after blocking Gal-9 or TIM-3. In summary, overexpression of Gal-9 on NK cells, which interacts with TIM-3⁺CD8⁺ T cells and likely contributes to antiviral CD8⁺ T cell dysfunction, may be a potential target for the treatment of CHB patients.

SUBMITTER: Liu S

PROVIDER: S-EPMC9301626 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Natural Killer Cells Induce CD8+ T Cell Dysfunction via Galectin-9/TIM-3 in Chronic Hepatitis B Virus Infection.

Liu Siyu S Xu Chang C Yang Fan F Zong Lu L Qin Yizu Y Gao Yufeng Y Su Qian Q Li Tuantuan T Li Ye Y Xu Yuanhong Y Zheng Meijuan M

Frontiers in immunology 20220628

The antiviral response of natural killer (NK) cells and CD8+ T cells is weak in patients with chronic hepatitis B (CHB) infection. However, the specific characteristics of these cells and the association between NK cells and CD8+ T cell dysfunction is not well known. In this study, higher galectin-9 (Gal-9) expression was observed in circulating NK cells from CHB patients than from healthy controls and was found to contribute to NK cell dysfunction. In addition, circulating ...[more]

PMID: 35874664

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Project description:Although persistent hepatitis B virus (HBV) infection is associated with natural killer (NK) cell dysfunction, it remains obscure whether HBV viral antigens are responsible for NK cell dysfunction in patients with chronic hepatitis B (CHB) infection. In this study, we found that the percentage of NK cells expressing the inhibitory receptor, NKG2A, was increased in CHB patients, and NKG2A blockade restored NK cell function. Furthermore, in CHB patients, the frequency of NK cells expressing NKG2A positively correlated with the number of regulatory T cells (Tregs) and production of interleukin-10 (IL-10) in these Tregs. Moreover, exposure of peripheral blood mononuclear cells (PBMCs) isolated from healthy controls to sera from CHB patients resulted in increased proportion of NKG2A+ NK cells; IL-10 blockade reduced the frequency of NKG2A+ NK cells while increasing the percentage of IFN-?+ NK cells. In addition, stimulation of NK cells and Tregs from healthy controls with CHB sera together with anti-IL-10 antibody increased IFN-? production in the culture supernatant. The frequencies of NKG2A+ NK cells and IL-10+ Tregs, along with serum levels of alanine transferase and HBV DNA, were significantly increased in CHB patients positive for the Hepatitis B e antigen (HBeAg, a marker of viral replication) when compared to HBeAg-negative CHB patients. Importantly, exposure of PBMCs from healthy controls to HBeAg resulted in increased IL-10 production but reduced levels of TNF and IFN-?, and IL-10 blockade rescued the generation of TNF and IFN-? in this assay. The reduced production of TNF and IFN-? was also observed in NK cells and Tregs from healthy controls that were stimulated with HBeAg, while IL-10 blockade increased the secretion of these two cytokines. We conclude that HBeAg induces IL-10 production in Tregs, thereby leading to increased expression of NKG2A on NK cells, which contributes to NK cell dysfunction during CHB infection. These data suggest that HBeAg is associated with NK cell dysfunction in CHB.

Dataset Information

Natural Killer Cells Induce CD8⁺ T Cell Dysfunction via Galectin-9/TIM-3 in Chronic Hepatitis B Virus Infection.

Publications

Natural Killer Cells Induce CD8<sup>+</sup> T Cell Dysfunction <i>via</i> Galectin-9/TIM-3 in Chronic Hepatitis B Virus Infection.

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