U.S. Department of Health and Human Services

Immunology Section

Barbara Rehermann, M.D., Chief

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Natural killer cells attenuate the virus-specific T cell response in chronic infectionNatural killer (NK) cells play a central role in the attenuation of virus-specific CD4 and CD8 T cell responses in chronic infection. The following mechanisms were discovered in the LCMV-model of chronic viral hepatitis (for a review see Nat Med. 2013;19:859-68): NK cells kill activated CD4 T cells in a perforin-dependent manner, which results in reduced CD4 help to CD8 T cells and exhaustion of the LCMV-specific T cell response after high dose LCMV infection. Additional mechanisms of CD8 T cell regulation include perforin-mediated lysis of activated CD8 T cells that upregulate NKG2D in response to IL-10, and TRAIL-mediated lysis of virus-specific CD8 T cells that upregulate TRAIL-R2. A negative feedback loop is the upregulation of CD48 on activated CD8 T cells, which inhibits lysis by NK cells via stimulation of the inhibitory NK cell receptor CD244 (2B4). NK cells also lyse hepatocytes and activated stellate cells with increased TRAIL-or decreased MHC-class I expression. The lysis of activated stellate cells may slow disease progression.Enlarge
Intracellular innate immune response to hepatitis C virusDouble figure depicting (A) the sensing of dsRNA structures by infected hepatocytes and (B) the induction of the antiviral state in neighboring hepatocytes. Hepatocytes sense double-stranded RNA (dsRNA) via the cytoplasmic pattern recognition receptor RIG-I and the endosomal pattern recognition receptor TLR3. Secreted IFN-beta induces an antiviral state in neighboring hepatocytes via JAK-STAT mediated signaling. HCV interferes with this pathway at multiple points (for a review see J Clin Invest 119: 1745-54).Enlarge