CD56+dim and CD56+bright cell activation and apoptosis in hepatitis C virus infection
A. W. LIN
Medicine and †Pediatrics, Weill Medical College of Cornell University, New York, USA
Search for more papers by this authorS. A. GONZALEZ
Medicine and †Pediatrics, Weill Medical College of Cornell University, New York, USA
Search for more papers by this authorS. CUNNINGHAM-RUNDLES
Center for the Study of Hepatitis C, Departments of
Search for more papers by this authorG. DORANTE
Medicine and †Pediatrics, Weill Medical College of Cornell University, New York, USA
Search for more papers by this authorS. MARSHALL
Medicine and †Pediatrics, Weill Medical College of Cornell University, New York, USA
Search for more papers by this authorA. TIGNOR
Medicine and †Pediatrics, Weill Medical College of Cornell University, New York, USA
Search for more papers by this authorC. HA
Medicine and †Pediatrics, Weill Medical College of Cornell University, New York, USA
Search for more papers by this authorI. M. JACOBSON
Medicine and †Pediatrics, Weill Medical College of Cornell University, New York, USA
Search for more papers by this authorCorresponding Author
A. H. TALAL
Medicine and †Pediatrics, Weill Medical College of Cornell University, New York, USA
Dr Andrew Talal, Weill Medical College of Cornell University, 525 E. 68th Street, A-354 New York, NY 10021, USA E-mail: [email protected]Search for more papers by this authorA. W. LIN
Medicine and †Pediatrics, Weill Medical College of Cornell University, New York, USA
Search for more papers by this authorS. A. GONZALEZ
Medicine and †Pediatrics, Weill Medical College of Cornell University, New York, USA
Search for more papers by this authorS. CUNNINGHAM-RUNDLES
Center for the Study of Hepatitis C, Departments of
Search for more papers by this authorG. DORANTE
Medicine and †Pediatrics, Weill Medical College of Cornell University, New York, USA
Search for more papers by this authorS. MARSHALL
Medicine and †Pediatrics, Weill Medical College of Cornell University, New York, USA
Search for more papers by this authorA. TIGNOR
Medicine and †Pediatrics, Weill Medical College of Cornell University, New York, USA
Search for more papers by this authorC. HA
Medicine and †Pediatrics, Weill Medical College of Cornell University, New York, USA
Search for more papers by this authorI. M. JACOBSON
Medicine and †Pediatrics, Weill Medical College of Cornell University, New York, USA
Search for more papers by this authorCorresponding Author
A. H. TALAL
Medicine and †Pediatrics, Weill Medical College of Cornell University, New York, USA
Dr Andrew Talal, Weill Medical College of Cornell University, 525 E. 68th Street, A-354 New York, NY 10021, USA E-mail: [email protected]Search for more papers by this authorSUMMARY
CD3–CD56+dim natural killer (NK) cells, which are cytotoxic against virally infected cells, may be important in hepatitis C virus (HCV)-infected patients who are successfully treated with pegylated interferon (PEG-IFN)-α. We used flow cytometry to enumerate activated (CD69+) and apoptotic (annexin-V+) dim (CD3–CD56+dim) and bright (CD3–CD56+bright) NK cells obtained from HCV-infected patients before treatment (n = 16) and healthy controls (n = 15) in the absence and presence of pegylated interferon (PEG-IFN)-α-2b. A subset of HCV-infected patients, subsequently treated with PEG-IFN-α-2b in vivo, was determined to have a sustained virological response (SVR, n = 6) or to not respond (NR) to treatment (n = 5). In the absence of IFN, activated dim (CD3–CD56+dim CD69+) NK cells were significantly decreased (P = 0·04) while activated apoptotic dim (CD3–CD56+dimCD69+annexin-V+) NK cells tended to be increased (P = 0·07) in SVR patients compared with NR patients. Activated bright (CD3–CD56+brightCD69+) and activated apoptotic bright (CD3–CD56+brightCD69+annexin-V+) NK cells were significantly correlated (P = 0·02 and P = 0·01, respectively) with increasing hepatic inflammation. These findings suggest that in the absence of PEG-IFN, activated dim (CD3–CD56+dimCD69+) NK cell turnover may be enhanced in SVR compared with NR patients and that activated bright (CD3–CD56+brightCD69+) NK cells may play a role in liver inflammation.
REFERENCES
- 1 Mehal WZ, Azzaroli F, Crispe IN. Immunology of the healthy liver: old questions and new insights. Gastroenterology 2001; 120: 250–60.
- 2
Biron CA,
Dalod M,
Salazar-Mather TP.
Innate Immunity and Viral Infections. In: SH Kaufmann,
A Sher,
R Ahmed, eds.
Immunology of Infectious Diseases. Washington DC: ASM Press, 2002: 139–60.
10.1128/9781555817978.ch11 Google Scholar
- 3 Cooper MA, Fehniger TA, Turner SC, Chen KS, Ghaheri BA, Ghayur T, Carson WE, Caligiuri MA. Human natural killer cells. a unique innate immunoregulatory role for the CD56 (bright) subset. Blood 2001; 97: 3146–51.
- 4 Fehniger TA, Cooper MA, Nuovo GJ, Cella M, Facchetti F, Colonna M, Caligiuri MA. CD56bright natural killer cells are present in human lymph nodes and are activated by T cell-derived IL-2: a potential new link between adaptive and innate immunity. Blood 2003; 101: 3052–7.
- 5 Campbell JJ, Qin S, Unutmaz D, Soler D, Murphy KE, Hodge MR, Wu L, Butcher EC. Unique subpopulations of CD56+ NK and NK-T peripheral blood lymphocytes identified by chemokine receptor expression repertoire. J Immunol 2001; 166: 6477–82.
- 6 Deignan T, Curry MP, Doherty DG et al. Decrease in hepatic CD56(+) T cells and V alpha 24(+) natural killer T cells in chronic hepatitis C viral infection. J Hepatol 2002; 37: 101–8.
- 7 Par G, Rukavina D, Podack ER et al. Decrease in CD3-negative-CD8dim(+) and Vdelta2/Vgamma9 TcR+ peripheral blood lymphocyte counts, low perforin expression and the impairment of natural killer cell activity is associated with chronic hepatitis C virus infection. J Hepatol 2002; 37: 514–22.
- 8 Yamagiwa S, Ichida T, Okoshi S et al. Serial Phenotypic profiling of intrahepatic lymphocytes in patients with chronic hepatitis C before and after combination interferon alfa-2B and ribavirin therapy. Hepatology 2003; 38: 460A.
- 9 Talal AH, Shata MT, Markatou M et al. Virus dynamics and immune responses during treatment in patients coinfected with hepatitis C and HIV. J Acquir Immune Defic Syndr 2004; 35: 103–13.
- 10 Appasamy R, Bryant J, Hassanein T, Van Thiel DH, Whiteside TL. Effects of therapy with interferon-alpha on peripheral blood lymphocyte subsets and NK activity in patients with chronic hepatitis C. Clin Immunol Immunopathol 1994; 73: 350–7.
- 11 Kaser A, Enrich B, Ludwiczek O, Vogel W, Tilg H. Interferon-alpha (IFN-alpha) enhances cytotoxicity in healthy volunteers and chronic hepatitis C infection mainly by the perforin pathway. Clin Exp Immunol 1999; 118: 71–7.
- 12 Malaponte G, Passero E, Leonardi S et al. Effect of alpha-interferon on natural killer cell activity and lymphocyte subsets in thalassemia patients with chronic hepatitis C. Acta Haematol 1997; 98: 83–8.
- 13 Jinushi M, Takehara T, Kanto T et al. Critical role of MHC class I-related chain A and B expression on IFN-alpha-stimulated dendritic cells in NK cell activation: impairment in chronic hepatitis C virus infection. J Immunol 2003; 170: 1249–56.
- 14 Manns MP, McHutchison JG, Gordon SC et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C. a randomised trial. Lancet 2001; 358: 958–65.
- 15 Fried MW, Shiffman ML, Reddy KR et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002; 347: 975–82.
- 16 Talal AH, Irwin CE, Dieterich DT, Yee H, Zhang L. Effect of HIV-1 infection on lymphocyte proliferation in gut-associated lymphoid tissue. J Acquir Immune Defic Syndr 2001; 26: 208–17.
- 17 Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR and DOSVIRC Groups. Lancet 1997; 349: 825–32.
- 18 Okamoto H, Okada S, Sugiyama Y, Kurai K, Iizuka H, Machida A, Miyakawa Y, Mayumi M. Nucleotide sequence of the genomic RNA of hepatitis C virus isolated from a human carrier: comparison with reported isolates for conserved and divergent regions. J General Virol 1991; 72: 2697–704.
- 19 Simmonds P, Alberti A, Alter HJ et al. A proposed system for the nomenclature of hepatitis C viral genotypes. Hepatology 1994; 19: 1321–4.
- 20 Simmonds P, Holmes EC, Cha TA et al. Classification of hepatitis C virus into six major genotypes and a series of subtypes by phylogenetic analysis of the NS-5 region. J General Virol 1993; 74 (11): 2391–9.
- 21
Raynal P,
Pollard HB.
Annexins. the problem of assessing the biological role for a gene family of multifunctional calcium- and phospholipid-binding proteins.
Biochim Biophys Acta
1994; 1197: 63–93.
10.1016/0304-4157(94)90019-1 Google Scholar
- 22 Bennett IM, Zatsepina O, Zamai L, Azzoni L, Mikheeva T, Perussia B. Definition of a natural killer NKR–P1A+/CD56–/CD16– functionally immature human NK cell subset that differentiates in vitro in the presence of interleukin 12. J Exp Med 1996; 184: 1845–56.
- 23 Loza MJ, Zamai L, Azzoni L, Rosati E, Perussia B. Expression of type 1 (interferon gamma) and type 2 (interleukin-13, interleukin-5) cytokines at distinct stages of natural killer cell differentiation from progenitor cells. Blood 2002; 99: 1273–81.
- 24 Clausen J, Vergeiner B, Enk M, Petzer AL, Gastl G, Gunsilius E. Functional significance of the activation-associated receptors CD25 and CD69 on human NK-cells and NK-like T-cells. Immunobiology 2003; 207: 85–93.
- 25 Borrego F, Robertson MJ, Ritz J, Pena J, Solana R. CD69 is a stimulatory receptor for natural killer cell and its cytotoxic effect is blocked by CD94 inhibitory receptor. Immunology 1999; 97: 159–65.
- 26 Martin SJ, Reutelingsperger CP, McGahon AJ, Rader JA, Van Schie RC, LaFace DM, Green DR. Early redistribution of plasma membrane phosphatidylserine is a general feature of apoptosis regardless of the initiating stimulus: inhibition by overexpression of Bcl-2 and Abl. J Exp Med 1995; 182: 1545–56.
- 27 Golden-Mason L, Asrafel H, Rosen HR, Madrigal-Estebas L, Doherty DG, Hegarty JE, O'Farrelly C. Peripheral Natural Killer (NK) cells are depleted and functionally impaired in chronic HCV infection. Hepatology 2003; 38: 458A.
- 28 Doherty DG, Norris S, Madrigal-Estebas L, McEntee G, Traynor O, Hegarty JE, O'Farrelly C. The human liver contains multiple populations of NK cells, T cells, and CD3+CD56+ natural T cells with distinct cytotoxic activities and Th1, Th2, and Th0 cytokine secretion patterns. J Immunol 1999; 163: 2314–21.
- 29 Arase H, Mocarski ES, Campbell AE, Hill AB, Lanier LL. Direct recognition of cytomegalovirus by activating and inhibitory NK cell receptors. Science 2002; 296: 1323–6.
- 30 Smith HR, Heusel JW, Mehta IK et al. Recognition of a virus-encoded ligand by a natural killer cell activation receptor. Proc Natl Acad Sci USA 2002; 99: 8826–31.
- 31 Brown MG, Dokun AO, Heusel JW et al. Vital involvement of a natural killer cell activation receptor in resistance to viral infection. Science 2001; 292: 934–7.
- 32 Herzer K, Falk CS, Encke J, Eichhorst ST, Ulsenheimer A, Seliger B, Krammer PH. Upregulation of major histocompatibility complex class I on liver cells by hepatitis C virus core protein via p53 and TAP1 impairs natural killer cell cytotoxicity. J Virol 2003; 77: 8299–309.
- 33 Kawarabayashi N, Seki S, Hatsuse K et al. Decrease of CD56(+) T Cells and Natural Killer Cells in Cirrhotic Livers With Hepatitis C May Be Involved in Their Susceptibility to Hepatocellular Carcinoma. Hepatology 2000; 32: 962–9.
- 34 Yonekura K, Ichida T, Sato K et al. Liver-infiltrating CD56 positive T lymphocytes in hepatitis C virus infection. Liver 2000; 20: 357–65.
- 35 Panasiuk A, Prokopowicz D, Zak J, Wysocka J. Peripheral blood T, B, and NK cells in relation to histological hepatitis activity and fibrosis stage in chronic hepatitis C. Hepatogastroenterology 2003; 50: 178–82.
- 36
Jacobs R,
Hintzen G,
Kemper A,
Beul K,
Kempf S,
Behrens G,
Sykora KW,
Schmidt RE.
CD56bright cells differ in their KIR repertoire and cytotoxic features from CD56dim NK cells.
Eur J Immunol
2001; 31: 3121–7.
10.1002/1521-4141(2001010)31:10<3121::AID-IMMU3121>3.0.CO;2-4 CAS PubMed Web of Science® Google Scholar
