Perforin, Fas/Fas ligand, and TNF-alpha pathways as specific and bystander killing mechanisms of hepatitis C virus-specific human CTL

• Published in: The Journal of immunology (1950) Vol. 158; no. 11; pp. 5283 - 5291
• Main Authors: Ando, K, Hiroishi, K, Kaneko, T, Moriyama, T, Muto, Y, Kayagaki, N, Yagita, H, Okumura, K, Imawari, M
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 01-06-1997
• Subjects: Antigen Presentation; Cytotoxicity, Immunologic; fas Receptor - immunology; Hepacivirus - immunology; Hepatitis C - immunology; hepatitis C virus; Humans; Membrane Glycoproteins - immunology; Perforin; Pore Forming Cytotoxic Proteins; Signal Transduction; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Cytotoxic - virology; Tumor Necrosis Factor-alpha - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.158.11.5283

In chronic hepatitis C, Fas expression is up-regulated in the hepatocytes, especially near liver-infiltrating lymphocytes, and Fas ligand is expressed on the lymphocytes. The presence of hepatitis C virus (HCV)-specific CTLs has been demonstrated both in peripheral blood and among liver-infiltrating lymphocytes of patients with chronic hepatitis C. We studied the killing mechanisms of HCV-specific human CTLs using target cells that were sensitive or resistant to agonistic anti-Fas Abs and TNF-alpha. We show that HCV-specific CTL clones kill non-Ag-bearing bystander cells as well as Ag-bearing cells, although the bystander killing is less efficient than the specific target cell killing, and the efficacy of the bystander killing of anti-Fas- and soluble TNF-alpha-sensitive cells is greater than that of resistant cells. We also show that the killing of Ag-presenting, sensitive cells is mediated by Fas ligand and TNF-alpha as well as perforin, although the latter plays a major role in the killing at a low E:T ratio, and that the killing of sensitive bystander cells is primarily mediated by Fas ligand and TNF-alpha on CTLs expressed upon specific Ag stimulation, which may be relevant to the bystander lysis by HCV-specific CTLs of uninfected hepatocytes, in which Fas expression is up-regulated. Activated CTLs also kill bystander cells by the perforin-based mechanism, although it requires a high E:T ratio. The effective bystander killing requires a close intercellular contact between CTLs and target cells, although TNF-alpha released from the CTLs mediates lysis of the bystander cells without a close cell-cell contact.