J. Exp. Med.
© The Rockefeller University Press
0022-1007/97/01/55/10 $2.00
Volume 185 January 1997 55-64

Macrophage-dependent Apoptosis of CD4⁺ T Lymphocytes from HIV-infected Individuals Is Mediated by FasL and Tumor Necrosis Factor

By Andrew D. Badley,^* David Dockrell,^* Margaret Simpson, Ron Schut, David H. Lynch,^§ Paul Leibson, and Carlos V. Paya^¶*

From the ^* Division of Infectious Diseases, ^¶ Division of Experimental Pathology, and  Department of Immunology, Mayo Clinic, Rochester, Minnesota 55901;  Division of Infectious Diseases, Hennepin County Medical Center, Minneapolis, Minnesota 55404; and ^§ Immunex Corporation, Seattle, Washington 98101

Apoptosis of bystander uninfected CD4⁺ T lymphocytes by neighboring HIV-infected cells is observed in cell culture and in lymphoid tissue of HIV-infected individuals. This study addresses whether antigen-presenting cells such as human macrophages mediate apoptosis of CD4⁺ T cells from HIV-infected individuals. Uninfected human macrophages, and to a larger degree, HIV-infected macrophages mediate apoptosis of T cells from HIV-infected, but not from uninfected control individuals. This macrophage-dependent killing targets CD4⁺, but not CD8⁺ T lymphocytes from HIV-infected individuals, and direct contact between macrophages and lymphocytes is required. Additional analyses indicated that the apoptosis-inducing ligands, FasL and tumor necrosis factor (TNF), mediate this macrophage-induced apoptosis of CD4⁺ T cells. These results support a role for macrophage-associated FasL and TNF in the selective depletion of CD4⁺ T cells in HIV-infected individuals.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Aquaro, S., Svicher, V., Schols, D., Pollicita, M., Antinori, A., Balzarini, J., Perno, C. F. (2006). Mechanisms underlying activity of antiretroviral drugs in HIV-1-infected macrophages: new therapeutic strategies. J. Leukoc. Biol. 80: 1103-1110 [Abstract] [Full Text]  
• Roeth, J. F., Collins, K. L. (2006). Human Immunodeficiency Virus Type 1 Nef: Adapting to Intracellular Trafficking Pathways. Microbiol. Mol. Biol. Rev. 70: 548-563 [Abstract] [Full Text]  
• Papasavvas, E., Sun, J., Luo, Q., Moore, E. C., Thiel, B., MacGregor, R. R., Minty, A., Mounzer, K., Kostman, J. R., Montaner, L. J. (2005). IL-13 Acutely Augments HIV-Specific and Recall Responses from HIV-1-Infected Subjects In Vitro by Modulating Monocytes. J. Immunol. 175: 5532-5540 [Abstract] [Full Text]  
• Aquaro, S., Svicher, V., Ceccherini-Silberstein, F., Cenci, A., Marcuccilli, F., Giannella, S., Marcon, L., Calio, R., Balzarini, J., Perno, C.-F. (2005). Limited development and progression of resistance of HIV-1 to the nucleoside analogue reverse transcriptase inhibitor lamivudine in human primary macrophages. J Antimicrob Chemother 55: 872-878 [Abstract] [Full Text]  
• Priceputu, E., Rodrigue, I., Chrobak, P., Poudrier, J., Mak, T. W., Hanna, Z., Hu, C., Kay, D. G., Jolicoeur, P. (2005). The Nef-Mediated AIDS-Like Disease of CD4C/Human Immunodeficiency Virus Transgenic Mice Is Associated with Increased Fas/FasL Expression on T Cells and T-Cell Death but Is Not Prevented in Fas-, FasL-, Tumor Necrosis Factor Receptor 1-, or Interleukin-1{beta}-Converting Enzyme-Deficient or Bcl2-Expressing Transgenic Mice. J. Virol. 79: 6377-6391 [Abstract] [Full Text]  
• Herbeuval, J.-P., Boasso, A., Grivel, J.-C., Hardy, A. W., Anderson, S. A., Dolan, M. J., Chougnet, C., Lifson, J. D., Shearer, G. M. (2005). TNF-related apoptosis-inducing ligand (TRAIL) in HIV-1-infected patients and its in vitro production by antigen-presenting cells. Blood 105: 2458-2464 [Abstract] [Full Text]  
• Wang, W.-H., Gregori, G., Hullinger, R. L., Andrisani, O. M. (2004). Sustained Activation of p38 Mitogen-Activated Protein Kinase and c-Jun N-Terminal Kinase Pathways by Hepatitis B Virus X Protein Mediates Apoptosis via Induction of Fas/FasL and Tumor Necrosis Factor (TNF) Receptor 1/TNF-{alpha} Expression. Mol. Cell. Biol. 24: 10352-10365 [Abstract] [Full Text]  
• De Rose, V., Cappello, P., Sorbello, V., Ceccarini, B., Gani, F., Bosticardo, M., Fassio, S., Novelli, F. (2004). IFN-{gamma} inhibits the proliferation of allergen-activated T lymphocytes from atopic, asthmatic patients by inducing Fas/FasL-mediated apoptosis. J. Leukoc. Biol. 76: 423-432 [Abstract] [Full Text]  
• Decrion, A.-Z., Varin, A., Estavoyer, J.-M., Herbein, G. (2004). CXCR4-mediated T cell apoptosis in human immunodeficiency virus infection. J. Gen. Virol. 85: 1471-1478 [Abstract] [Full Text]  
• Holm, G. H., Zhang, C., Gorry, P. R., Peden, K., Schols, D., De Clercq, E., Gabuzda, D. (2004). Apoptosis of Bystander T Cells Induced by Human Immunodeficiency Virus Type 1 with Increased Envelope/Receptor Affinity and Coreceptor Binding Site Exposure. J. Virol. 78: 4541-4551 [Abstract] [Full Text]  
• Garaci, E., Aquaro, S., Lapenta, C., Amendola, A., Spada, M., Covaceuszach, S., Perno, C.-F., Belardelli, F. (2003). Anti-nerve growth factor Ab abrogates macrophage-mediated HIV-1 infection and depletion of CD4+ T lymphocytes in hu-SCID mice. Proc. Natl. Acad. Sci. USA 100: 8927-8932 [Abstract] [Full Text]  
• Jekle, A., Keppler, O. T., De Clercq, E., Schols, D., Weinstein, M., Goldsmith, M. A. (2003). In Vivo Evolution of Human Immunodeficiency Virus Type 1 toward Increased Pathogenicity through CXCR4-Mediated Killing of Uninfected CD4 T Cells. J. Virol. 77: 5846-5854 [Abstract] [Full Text]  
• Mor, G., Sapi, E., Abrahams, V. M., Rutherford, T., Song, J., Hao, X.-Y., Muzaffar, S., Kohen, F. (2003). Interaction of the Estrogen Receptors with the Fas Ligand Promoter in Human Monocytes. J. Immunol. 170: 114-122 [Abstract] [Full Text]  
• Epelman, S., Neely, G. G., Ma, L. L., Gjomarkaj, M., Pace, E., Melis, M., Woods, D. E., Mody, C. H. (2002). Distinct fates of monocytes and T cells directly activated by Pseudomonas aeruginosa exoenzyme S. J. Leukoc. Biol. 71: 458-468 [Abstract] [Full Text]  
• de Oliveira Pinto, L. M., Garcia, S., Lecoeur, H., Rapp, C., Gougeon, M.-L. (2002). Increased sensitivity of T lymphocytes to tumor necrosis factor receptor 1 (TNFR1)- and TNFR2-mediated apoptosis in HIV infection: relation to expression of Bcl-2 and active caspase-8 and caspase-3. Blood 99: 1666-1675 [Abstract] [Full Text]  
• Lu, G., Janjic, B. M., Janjic, J., Whiteside, T. L., Storkus, W. J., Vujanovic, N. L. (2002). Innate Direct Anticancer Effector Function of Human Immature Dendritic Cells. II. Role of TNF, Lymphotoxin-{alpha}1{beta}2, Fas Ligand, and TNF-Related Apoptosis-Inducing Ligand. J. Immunol. 168: 1831-1839 [Abstract] [Full Text]  
• Lu, W., Achour, A., Arlie, M., Cao, L., Andrieu, J.-M. (2001). Enhanced Dendritic Cell-Driven Proliferation and Anti-HIV Activity of CD8+ T Cells by a New Phenothiazine Derivative, Aminoperazine. J. Immunol. 167: 2929-2935 [Abstract] [Full Text]  
• Roggero, R., Robert-Hebmann, V., Harrington, S., Roland, J., Vergne, L., Jaleco, S., Devaux, C., Biard-Piechaczyk, M. (2001). Binding of Human Immunodeficiency Virus Type 1 gp120 to CXCR4 Induces Mitochondrial Transmembrane Depolarization and Cytochrome c-Mediated Apoptosis Independently of Fas Signaling. J. Virol. 75: 7637-7650 [Abstract] [Full Text]  
• Shi, J., Gilbert, G. E., Kokubo, Y., Ohashi, T. (2001). Role of the liver in regulating numbers of circulating neutrophils. Blood 98: 1226-1230 [Abstract] [Full Text]  
• Lane, B. R., Strieter, R. M., Coffey, M. J., Markovitz, D. M. (2001). Human Immunodeficiency Virus Type 1 (HIV-1)-Induced GRO-{alpha} Production Stimulates HIV-1 Replication in Macrophages and T Lymphocytes. J. Virol. 75: 5812-5822 [Abstract] [Full Text]  
• Nwakoby, I. E., Reddy, K., Patel, P., Shah, N., Sharma, S., Bhaskaran, M., Gibbons, N., Kapasi, A. A., Singhal, P. C. (2001). Fas-Mediated Apoptosis of Neutrophils in Sera of Patients with Infection. Infect. Immun. 69: 3343-3349 [Abstract] [Full Text]  
• Dzialo-Hatton, R., Milbrandt, J., Hockett, R. D. Jr., Weaver, C. T. (2001). Differential Expression of Fas Ligand in Th1 and Th2 Cells Is Regulated by Early Growth Response Gene and NF-AT Family Members. J. Immunol. 166: 4534-4542 [Abstract] [Full Text]  
• Cannavo', G., Paiardini, M., Galati, D., Cervasi, B., Montroni, M., De Vico, G., Guetard, D., Bocchino, M. L., Picerno, I., Magnani, M., Silvestri, G., Piedimonte, G. (2001). Abnormal intracellular kinetics of cell-cycle-dependent proteins in lymphocytes from patients infected with human immunodeficiency virus: a novel biologic link between immune activation, accelerated T-cell turnover, and high levels of apoptosis. Blood 97: 1756-1764 [Abstract] [Full Text]  
• Kamradt, T., Mitchison, N. A. (2001). Tolerance and Autoimmunity. NEJM 344: 655-664 [Full Text]  
• AGOSTINI, C., SIVIERO, M., FACCO, M., CAROLLO, D., BINOTTO, G., TOSONI, A., CATTELAN, A. M., ZAMBELLO, R., TRENTIN, L., SEMENZATO, G. (2001). Antiapoptotic Effects of IL-15 on Pulmonary Tc1 Cells of Patients with Human Immunodeficiency Virus Infection. Am. J. Respir. Crit. Care Med. 163: 484-489 [Abstract] [Full Text]  
• Mahlknecht, U., Deng, C., Lu, M. C., Greenough, T. C., Sullivan, J. L., O'Brien, W. A., Herbein, G. (2000). Resistance to Apoptosis in HIV-Infected CD4+ T Lymphocytes Is Mediated by Macrophages: Role for Nef and Immune Activation in Viral Persistence. J. Immunol. 165: 6437-6446 [Abstract] [Full Text]  
• Badley, A. D., Pilon, A. A., Landay, A., Lynch, D. H. (2000). Mechanisms of HIV-associated lymphocyte apoptosis. Blood 96: 2951-2964 [Abstract] [Full Text]  
• Aquaro, S., Panti, S., Caroleo, M. C., Balestra, E., Cenci, A., Forbici, F., Ippolito, G., Mastino, A., Testi, R., Mollace, V., Calio, R., Perno, C. F. (2000). Primary macrophages infected by human immunodeficiency virus trigger CD95-mediated apoptosis of uninfected astrocytes. J. Leukoc. Biol. 68: 429-435 [Abstract] [Full Text]  
• Darcissac, E. C. A., Truong, M.-J., Dewulf, J., Mouton, Y., Capron, A., Bahr, G. M. (2000). The Synthetic Immunomodulator Murabutide Controls Human Immunodeficiency Virus Type 1 Replication at Multiple Levels in Macrophages and Dendritic Cells. J. Virol. 74: 7794-7802 [Abstract] [Full Text]  
• Epelman, S., Bruno, T. F., Neely, G. G., Woods, D. E., Mody, C. H. (2000). Pseudomonas aeruginosa Exoenzyme S Induces Transcriptional Expression of Proinflammatory Cytokines and Chemokines. Infect. Immun. 68: 4811-4814 [Abstract] [Full Text]  
• Kremer, L., Estaquier, J., Wolowczuk, I., Biet, F., Ameisen, J.-C., Locht, C. (2000). Ineffective Cellular Immune Response Associated with T-Cell Apoptosis in Susceptible Mycobacterium bovis BCG-Infected Mice. Infect. Immun. 68: 4264-4273 [Abstract] [Full Text]  
• Tateyama, M., Oyaizu, N., McCloskey, T. W., Than, S., Pahwa, S. (2000). CD4 T lymphocytes are primed to express Fas ligand by CD4 cross-linking and to contribute to CD8 T-cell apoptosis via Fas/FasL death signaling pathway. Blood 96: 195-202 [Abstract] [Full Text]  
• Somma, F., Tuosto, L., Montani, M. S. G., Di Somma, M. M., Cundari, E., Piccolella, E. (2000). Engagement of CD4 Before TCR Triggering Regulates Both Bax- and Fas (CD95)-Mediated. J. Immunol. 164: 5078-5087 [Abstract] [Full Text]  
• Herbein, G., O'brien, W. A. (2000). Tumor Necrosis Factor (TNF)-{alpha} and TNF Receptors in Viral Pathogenesis. Exp. Biol. Med. 223: 241-257 [Abstract] [Full Text]  
• Duffield, J. S., Erwig, L.-P., Wei, X.-q., Liew, F. Y., Rees, A. J., Savill, J. S. (2000). Activated Macrophages Direct Apoptosis and Suppress Mitosis of Mesangial Cells. J. Immunol. 164: 2110-2119 [Abstract] [Full Text]  
• Knutsen, A. P., Roodman, S. T., Freeman, J. J., Mueller, K. R., Bouhasin, J. D. (1999). Inhibition of Thymopoiesis of CD34+ Cell Maturation by HIV-1 in an In Vitro CD34+ Cell and Thymic Epithelial Organ Culture Model. Stem Cells 17: 327-338 [Abstract] [Full Text]  
• Shankar, P., Xu, Z., Lieberman, J. (1999). Viral-Specific Cytotoxic T Lymphocytes Lyse Human Immunodeficiency Virus-Infected Primary T Lymphocytes by the Granule Exocytosis Pathway. Blood 94: 3084-3093 [Abstract] [Full Text]  
• Bohler, T., Debatin, K.-M., Linde;, R., Pahwa, S., McCloskey, T. W. (1999). Sensitivity of CD4+ Peripheral Blood T Cells Toward Spontaneous and CD95 (APO-1/Fas)-Induced Apoptosis in Pediatric Human Immunodeficiency Virus Infection. Blood 94: 1829-1833 [Full Text]  
• Hadida, F., Vieillard, V., Mollet, L., Clark-Lewis, I., Baggiolini, M., Debre, P. (1999). Cutting Edge: RANTES Regulates Fas Ligand Expression and Killing by HIV-Specific CD8 Cytotoxic T Cells. J. Immunol. 163: 1105-1109 [Abstract] [Full Text]  
• Singh, R. K., Varney, M. L., Buyukberber, S., Ino, K., Ageitos, A. G., Reed, E., Tarantolo, S., Talmadge, J. E. (1999). Fas-FasL-mediated CD4+ T-Cell Apoptosis following Stem Cell Transplantation. Cancer Res. 59: 3107-3111 [Abstract] [Full Text]  
• Bailer, R. T., Holloway, A., Sun, J., Margolick, J. B., Martin, M., Kostman, J., Montaner, L. J. (1999). IL-13 and IFN-{gamma} Secretion by Activated T Cells in HIV-1 Infection Associated with Viral Suppression and a Lack of Disease Progression. J. Immunol. 162: 7534-7542 [Abstract] [Full Text]  
• Yin, C., Wu, M. S., Pauza, C. D., Salvato, M. S. (1999). High Major Histocompatibility Complex-Unrestricted Lysis of Simian Immunodeficiency Virus Envelope-Expressing Cells Predisposes Macaques to Rapid AIDS Progression. J. Virol. 73: 3692-3701 [Abstract] [Full Text]  
• Griffith, T. S., Wiley, S. R., Kubin, M. Z., Sedger, L. M., Maliszewski, C. R., Fanger, N. A. (1999). Monocyte-mediated Tumoricidal Activity via the Tumor Necrosis Factor-related Cytokine, TRAIL. JEM 189: 1343-1354 [Abstract] [Full Text]  
• Gómez del Moral, M., Ortuño, E., Fernández-Zapatero, P., Alonso, F., Alonso, C., Ezquerra, A., Domínguez, J. (1999). African Swine Fever Virus Infection Induces Tumor Necrosis Factor Alpha Production: Implications in Pathogenesis. J. Virol. 73: 2173-2180 [Abstract] [Full Text]  
• Van Hoffen, E., Van Wichen, D. F., Leemans, J. C., Broekhuizen, R. A.J.F., Bruggink, A. H., De Boer, M., De Jonge, N., Kirkels, H., Slootweg, P. J., Gmelig-Meyling, F. H.J., De Weger, R. A. (1998). T Cell Apoptosis in Human Heart Allografts : Association with Lack of Co-Stimulation?. Am. J. Pathol. 153: 1813-1824 [Abstract] [Full Text]  
• McCloskey, T. W., Bakshi, S., Than, S., Arman, P., Pahwa, S. (1998). Immunophenotypic Analysis of Peripheral Blood Mononuclear Cells Undergoing In Vitro Apoptosis After Isolation From Human Immunodeficiency Virus-Infected Children. Blood 92: 4230-4237 [Abstract] [Full Text]  
• Davis, I. C., Girard, M., Fultz, P. N. (1998). Loss of CD4+ T Cells in Human Immunodeficiency Virus Type 1-Infected Chimpanzees Is Associated with Increased Lymphocyte Apoptosis. J. Virol. 72: 4623-4632 [Abstract] [Full Text]  
• Algeciras, A., Dockrell, D. H., Lynch, D. H., Paya, C. V. (1998). CD4 Regulates Susceptibility to Fas ligand- and Tumor Necrosis Factor-mediated Apoptosis. JEM 187: 711-720 [Abstract] [Full Text]  
• Holtz-Heppelmann, C. J., Algeciras, A., Badley, A. D., Paya, C. V. (1998). Transcriptional Regulation of the Human FasL Promoter-Enhancer Region. J. Biol. Chem. 273: 4416-4423 [Abstract] [Full Text]  
• Ferrante, P., Fusi, M. L., Saresella, M., Caputo, D., Biasin, M., Trabattoni, D., Salvaggio, A., Clerici, E., de Vries, J. E., Aversa, G., Cazzullo, C. L., Clerici, M. (1998). Cytokine Production and Surface Marker Expression in Acute and Stable Multiple Sclerosis: Altered IL-12 Production and Augmented Signaling Lymphocytic Activation Molecule (SLAM)-Expressing Lymphocytes in Acute Multiple Sclerosis. J. Immunol. 160: 1514-1521 [Abstract] [Full Text]  
• Herbein, G., Van Lint, C., Lovett, J. L., Verdin, E. (1998). Distinct Mechanisms Trigger Apoptosis in Human Immunodeficiency Virus Type 1-Infected and in Uninfected Bystander T Lymphocytes. J. Virol. 72: 660-670 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS