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Prof. Zhigang Tian and Hui Peng’s group revealed a negative regulatory role of liver-resident NK cells

 

Recently, the research group directed by Prof. Zhigang Tian and Hui Peng published an article in Immunity, entitled “Liver-resident NK cells control antiviral activity of hepatic T cells via PD-1/PD-L1 axis”. This study found a negative regulatory role of liver-resident NK cells in antiviral hepatic T cell responses and revealed the underlying mechanisms.

The liver is an immune tolerant organ. Many types of viruses can exploit the immunosuppressive liver microenvironment to establish life-long viral persistence. The tolerogenic microenvironment of the liver is associated with impaired T cell responses, but the precise cellular and molecular mechanisms underlying impaired T cell responses in hepatic tolerance induction is not fully elucidated. In 2013, Prof Zhigang Tian’s group found that the adult mouse liver contained a unique NK cell subset, namely “liver-resident NK (LrNK) cells” (J Clin Invest, 2013). LrNK cells account for nearly half of the hepatic bulk NK cells, and differ from circulating conventional NK (cNK) cells in developmental pathways and expression profiles of effector molecules. Genomic analysis revealed that LrNK cells had a significantly higher enrichment of genes involved in negative regulation of the immune response than cNK cells. Based on these facts, the researchers speculated that LrNK cells might be involved in maintaining liver immune tolerance through regulating T cell responses.

By using LrNK cell-deficient mice, the researchers found that the absence of LrNK cells led to enhanced hepatic T cell functions, decreased viral loads and exacerbated liver injury during viral infection. Adoptive transfer of LrNK cells into WT or LrNK cell-deficient mice could inhibited antiviral responses of hepatic NK cells, while cNK cells had the opposite effect. The researchers also found that LrNK cells upregulated PD-L1 expression following viral infection. By blockade of PD-L1 on LrNK cells or adoptive transfer of PD-1-deficient T cells, they further demonstrated LrNK cells negatively regulate antiviral T cell responses via a PD-L1-dependent mechanism. Therefore, this study reveals distinct functions of LrNK and cNK cells in shaping T cell responses, and suggests a role of LrNK cells in maintaining liver immune tolerance. Considering the differential compositions of NK cell subsets in different tissues, this study has profound implications for our understanding of the specific features of local immunity.

Prof. Zhigang Tian and Hui Peng are the corresponding authors of this paper, and Dr. Jing Zhou is the first author. Prof. Yuzhang Wu and Prof. Lilin Ye of Third Military Medical University, and Prof. Zhongjun Dong of Tsinghua University also contributed to this research. Funding sources of this research include the National Natural Science Foundation of China and the Chinese Academy of Sciences.