Regulatory NK cells mediated between immunosuppressive monocytes and dysfunctional T cells in chronic HBV infection

Abstract

Background and aimsHBV infection represents a major health problem worldwide, but the immunological mechanisms by which HBV causes chronic persistent infection remain only partly understood. Recently, cell subsets with suppressive features have been recognised among monocytes and natural killer (NK) cells. Here we examine the effects of HBV on monocytes and NK cells.MethodsMonocytes and NK cells derived from chronic HBV-infected patients and healthy controls were purified and characterised for phenotype, gene expression and cytokines secretion by flow cytometry, quantitative real-time (qRT)-PCR, ELISA and western blotting. Culture and coculture of monocytes and NK cells were used to determine NK cell activation, using intracellular cytokines staining.ResultsIn chronic HBV infection, monocytes express higher levels of PD-L1, HLA-E, interleukin (IL)-10 and TGF-β, and NK cells express higher levels of PD-1, CD94 and IL-10, compared with healthy individuals. HBV employs hepatitis B surface antigen (HBsAg) to induce suppressive monocytes with HLA-E, PD-L1, IL-10 and TGF-β expression via the MyD88/NFκB signalling pathway. HBV-treated monocytes induce NK cells to produce IL-10, via PD-L1 and HLA-E signals. Such NK cells inhibit autologous T cell activation.ConclusionsOur findings reveal an immunosuppressive cascade, in which HBV generates suppressive monocytes, which initiate regulatory NK cells differentiation resulting in T cell inhibition.

CD56−CD16+ NK cells from HIV-infected individuals negatively regulate IFN-γ production by autologous CD8+ T cells

“…Further, we illustrate that increased production of IL‐10 and TGF‐β inhibits the function of CD56 − CD16 + NK cells on CD8 + T cells in HIV‐infected individuals. Similar to our results, Li et al . found that during HBV infection, IL‐10 producing NK cells could inhibit T cell function.…”

“…During mouse cytomegalovirus infection, mouse total NK cells secrete IL‐10, leading to reduced IFN‐γ production by CD8 + T cells . In addition, HBV‐induced NK cells inhibit IFN‐γ production by autologous CD8 + T cells in an IL‐10‐dependent manner . Moreover, total NK cells exhibit negatively regulatory functions in infected individuals; we observed that CD56 − CD16 + NK cells produced more IL‐10 and TGF‐β in HIV‐infected individuals, and our data demonstrate that CD56 − CD16 + NK cells can inhibit IFN‐γ production by CD8 + T cells, the major effector cells against HIV infection.…”

T‐bet and Eomes govern differentiation and function of mouse and human NK cells and ILC1

“…Further studies will be needed to test if this also applies to exhausted NK cells in the context of chronic infection. A recent paper described that exhausted NK cells in HBV individuals express lower levels of T‐BET mRNA than NK cells from healthy donors , which is a first hint that similar exhaustion mechanisms may be at play in NK and T cells during chronic infections.…”

Insights for clinical diagnostic indicators of virus and host in chronic hepatitis B infection

“…This phenotype was similar in monocytes‐derived macrophages . Li et al suggested that HBsAg enabled monocytes to highly express cell surface inhibitors (PD‐L1 and HLA‐E) and anti‐inflammatory factors (TNF‐α, TGF‐β and IL‐10) to interact with NK cells, which led to regulatory NK cells differentiation, further inhibited T‐cell activation.…”