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CUTTING EDGE |
Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA
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| Introduction |
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One of the most widely studied regulators of cell death is the Bcl-2 superfamily. This family is composed of more than 15 family members in humans, mice, and worms. Some members of the family are proapoptotic (Bad, Bax, Bid) while others (Bcl-2 and Bcl-xL) exhibit anti-apoptotic functions (6). At any given time, a cells susceptibility to apoptosis is determined by a ratio of the pro- to anti-apoptotic factors. The prototypic member of this gene family is Bcl-2. Originally identified as a translocation in B cell lymphoma (7), overexpression of Bcl-2 provides protection against cell death by preventing release of cytochrome c after mitochondrial damage (8).
Several studies have shown that Bcl-2 plays a role in T cell survival. The most compelling evidence comes from the observation that Bcl-2-/- mice exhibit rapid loss of peripheral T cells (9, 10). Also, it has been shown that activated T cells that exhibit increased susceptibility to apoptosis in vitro express lower levels of Bcl-2 (11). However, very little is known about Bcl-2 expression in Ag-specific T cells in vivo. In this study, we have examined the expression of Bcl-2 in CD8 T cells as they progress through the various stages of the immune response (naive to effector to memory) following infection of mice with lymphocytic choriomeningitis virus (LCMV).4 Using a transgenic T cell system and MHC class I tetramers to identify virus-specific CD8 T cells in normal mice, we show that memory CD8 T cells express higher levels of Bcl-2 than naive T cells. This finding suggests that Bcl-2 may play a role in the long-term survival of memory CD8 T cells.
| Materials and Methods |
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Six- to 8-wk-old female BALB/c or C57BL/6 mice were purchased from The Jackson Laboratory (Bar Harbor, ME). Mice were infected with 2 x 105 PFU of LCMV Armstrong strain i.p. and used at the indicated time points. Virus stocks were grown and quantitated as described previously (12).
Priming of transgenic cells
Priming of P14 transgenic cells has been described before (13). The LCMV TCR P14 transgenic mice (B6 x 129) were obtained from The Jackson Laboratory and then backcrossed to C57BL/6 at Emory University. The transgenic mice used in this study were backcrossed six to eight times. Briefly 2 x 106 naive P14 splenocytes were injected i.v. into naive C57BL/6 hosts. Four hours after transfer, mice were infected with 2 x 105 PFU of LCMV Armstrong i.p. and used at the indicated time points.
Flow cytometry and FACS analysis
Preparation of cells and staining has been described previously (1).
Intracellular staining for Bcl-2
Cells (2 x 106) were surface stained as described above. After washing unbound Ab and MHC class I tetramer, the cells were subjected to intracellular staining for Bcl-2 using the CytoFix/Cytoperm kit according to the manufacturers instructions (PharMingen, San Diego, CA). For intracellular Bcl-2 staining, FITC-conjugated hamster anti-mouse Bcl-2 Ab (clone 3F11) or its isotype control Ab (hamster IgG) (PharMingen) was used.
Preparation of H-2Db and H-2Ld tetramers
The construction and purification of LdNP118-126, DbGP33-41, DbNP396-404, and DbGP276-86 MHC class I tetramers have been described previously (1).
| Results |
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(data not
shown). Memory cells (79 days postinfection) contained higher levels of
Bcl-2 than those found in naive or effector cells.
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| Discussion |
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What are the implications of higher Bcl-2 expression in CD8 memory T cells? To understand what Bcl-2 may be doing, it is critical to note some differences between memory and naive cells. Memory cells survive for extended periods in vivo and exhibit a higher rate of homeostatic proliferation than naive cells (3). Little is known about the rate of progression through the phases of the cell cycle in these cells. Previous studies of Bcl-2 overexpression have shown that higher levels of Bcl-2 correlate with an extended G1 phase (14). Additionally, Ag-induced cell death in vitro has been demonstrated to occur from a late G1 phase cell cycle checkpoint that can be blocked by expression of p16INK4a or by inactivation of the retinoblastoma tumor suppressor protein (pRb) (15). The Bcl-2 levels in memory cells could increase G1 phase, allowing the cell to repair damage accrued over its long life span and then to rapidly progress through the rest of the cycle. The higher rate of homeostatic proliferation observed in memory cells may simply be a consequence of increased survival of the G1 phase transition. The increased levels of Bcl-2 found in memory cells may also influence survival of these cells after they encounter Ag upon reinfection. The higher levels of Bcl-2 may lead to a diminished death phase after secondary infection, resulting in a net increase of memory cells.
Our studies confirm and extend previous findings of Bcl-2 expression in activated T cells in vitro and in vivo. Activation of T cells in vitro with strong mitogenic stimuli and IL-2 results in slightly increased levels of Bcl-2 (11, 16, 17). In LCMV infection, we only observe decreases in Bcl-2 after prolonged expansion and proliferation. Ag-specific cells 5 days postinfection contain basal levels of Bcl-2 but with further proliferation contain low levels by 8 days postinfection. This maintenance of basal levels of Bcl-2 after early TCR activation makes teleological sense. If Bcl-2 decreased immediately after TCR activation, then cells would be deleted and a chronic infection would ensue. Additionally, our findings extend observations made in CD8 T cells from EBV and HIV patients (18, 19). CD8 T cells from patients generally had Bcl-2 levels lower than those found in uninfected controls. In these studies, the cells are of undefined specificity but they exhibit lower levels of Bcl-2 similar to Ag-specific cells at the peak of LCMV infection.
We also addressed differences between naive and memory phenotype cells of undefined specificity for both CD8 and CD4 cells. CD8 cells of a memory phenotype (CD8+CD44high) contained higher levels of Bcl-2 than the naive phenotype (CD8+CD44low), mirroring our observations with Ag-specific memory cells. Examination of CD4 naive and memory phenotype (CD4+CD44low vs CD4+CD44high) revealed no major differences between these two populations in Bcl-2 expression. This is consistent with the findings of Garcia et al. (20). Using transgenic CD4 T cells (specific to C5 complement protein), they monitored a CD4 response in vivo and found that Bcl-2 levels decrease in effector T cells and then return to normal levels in memory CD4 T cells (similar to those seen in naive cells). The difference in Bcl-2 expression between memory CD4 and CD8 T cells can be potentially explained through two mechanisms. Bcl-2 may be more of a critical survival factor for CD8 than CD4 T cells. Null mutants of the Bcl-2 gene lose most of their lymphocytes by the fourth week of life. Additionally, lymphocytes from these animals show impaired survival in vitro. Both of these defects are manifested more prominently in CD8 than in CD4 T cells (10). Another possible reason for the discrepancy in Bcl-2 levels is differences in cycling rate. As mentioned earlier, Bcl-2 is expressed more highly in Ag-specific memory than naive CD8 T cells. Memory CD8 T cells also have a higher rate of homeostatic proliferation than memory CD4 cells (K. Murali-Krishna and R. Ahmed, unpublished observations), suggesting a potential link between division rate in vivo and Bcl-2 expression. However, it should be noted that definitive analysis of Bcl-2 levels in Ag-specific memory CD4+ T cells will require the use of MHC class II tetramers to directly identify the Ag-specific cells.
Apoptosis is a complex multifactorial process controlled by interactions between pro- and anti-apoptotic genes. In this study, we have focused on the expression of one of the most important genes controlling apoptosis but future studies are needed to understand the roles of other genes such as Bcl-x, Bad, and Bax in controlling CD8 responses. We observed that Ag-specific memory cells contain increased Bcl-2, although effector cells are Bcl-2low. Understanding the mechanism by which a population of cells expressing high levels of Bcl-2 (memory) is generated from cells with low levels (effector) is a current endeavor in our laboratory. In addition, determining whether Bcl-2 is necessary for the generation and maintenance of CD8 memory T cells will require the generation of chimeras with CD8 T cells that lack Bcl-2. Finally, further studies are needed to determine whether the higher levels of Bcl-2 found in memory cells renders them more resistant than naive cells to apoptotic stimuli.
| Footnotes |
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2 Current address: Department of Microbiology, University of Alabama, Birmingham, AL 35294. ![]()
3 Address correspondence and reprint requests to Dr. Rafi Ahmed, Emory University School of Medicine, G211 Rollins Research Building, 1510 Clifton Road, Atlanta, GA 30322. E-mail address: ![]()
4 Abbreviation used in this paper: LCMV, lymphocytic choriomeningitis virus. ![]()
Received for publication January 7, 2000. Accepted for publication February 17, 2000.
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M. V. D. Soares, F. J. Plunkett, C. S. Verbeke, J. E. Cook, J. M. Faint, L. L. Belaramani, J. M. Fletcher, N. Hammerschmitt, M. Rustin, W. Bergler, et al. Integration of apoptosis and telomere erosion in virus-specific CD8+ T cells from blood and tonsils during primary infection Blood, January 1, 2004; 103(1): 162 - 167. [Abstract] [Full Text] [PDF] |
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S. Ilangumaran, S. Ramanathan, J. La Rose, P. Poussier, and R. Rottapel Suppressor of Cytokine Signaling 1 Regulates IL-15 Receptor Signaling in CD8+CD44high Memory T Lymphocytes J. Immunol., September 1, 2003; 171(5): 2435 - 2445. [Abstract] [Full Text] [PDF] |
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J. M. Grayson, N. G. Laniewski, J. G. Lanier, and R. Ahmed Mitochondrial Potential and Reactive Oxygen Intermediates in Antigen-Specific CD8+ T Cells During Viral Infection J. Immunol., May 1, 2003; 170(9): 4745 - 4751. [Abstract] [Full Text] [PDF] |
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K. M. Kerksiek, A. Ploss, I. Leiner, D. H. Busch, and E. G. Pamer H2-M3-Restricted Memory T Cells: Persistence and Activation Without Expansion J. Immunol., February 15, 2003; 170(4): 1862 - 1869. [Abstract] [Full Text] [PDF] |
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J. Kelly, R. Spolski, K. Imada, J. Bollenbacher, S. Lee, and W. J. Leonard A Role for Stat5 in CD8+ T Cell Homeostasis J. Immunol., January 1, 2003; 170(1): 210 - 217. [Abstract] [Full Text] [PDF] |
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M. P. Rubinstein, A. N. Kadima, M. L. Salem, C. L. Nguyen, W. E. Gillanders, and D. J. Cole Systemic Administration of IL-15 Augments the Antigen-Specific Primary CD8+ T Cell Response Following Vaccination with Peptide-Pulsed Dendritic Cells J. Immunol., November 1, 2002; 169(9): 4928 - 4935. [Abstract] [Full Text] [PDF] |
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H.-H. Xue, P. E. Kovanen, C. A. Pise-Masison, M. Berg, M. F. Radovich, J. N. Brady, and W. J. Leonard IL-2 negatively regulates IL-7 receptor alpha chain expression in activated T lymphocytes PNAS, October 15, 2002; 99(21): 13759 - 13764. [Abstract] [Full Text] [PDF] |
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B. Pantenburg, F. Heinzel, L. Das, P. S. Heeger, and A. Valujskikh T Cells Primed by Leishmania major Infection Cross-React with Alloantigens and Alter the Course of Allograft Rejection J. Immunol., October 1, 2002; 169(7): 3686 - 3693. [Abstract] [Full Text] [PDF] |
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J. M. Grayson, L. E. Harrington, J. G. Lanier, E. J. Wherry, and R. Ahmed Differential Sensitivity of Naive and Memory CD8+ T Cells to Apoptosis in Vivo J. Immunol., October 1, 2002; 169(7): 3760 - 3770. [Abstract] [Full Text] [PDF] |
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P. J. Dunne, J. M. Faint, N. H. Gudgeon, J. M. Fletcher, F. J. Plunkett, M. V. D. Soares, A. D. Hislop, N. E. Annels, A. B. Rickinson, M. Salmon, et al. Epstein-Barr virus-specific CD8+ T cells that re-express CD45RA are apoptosis-resistant memory cells that retain replicative potential Blood, July 18, 2002; 100(3): 933 - 940. [Abstract] [Full Text] [PDF] |
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Y. Nakamoto, S. Kaneko, and K. Kobayashi Increased susceptibility to apoptosis and attenuated Bcl-2 expression in T lymphocytes and monocytes from patients with advanced chronic hepatitis C J. Leukoc. Biol., July 1, 2002; 72(1): 49 - 55. [Abstract] [Full Text] [PDF] |
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T. M. Onami, L. E. Harrington, M. A. Williams, M. Galvan, C. P. Larsen, T. C. Pearson, N. Manjunath, L. G. Baum, B. D. Pearce, and R. Ahmed Dynamic Regulation of T Cell Immunity by CD43 J. Immunol., June 15, 2002; 168(12): 6022 - 6031. [Abstract] [Full Text] [PDF] |
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M. P. Davenport, C. Fazou, A. J. McMichael, and M. F. C. Callan Clonal Selection, Clonal Senescence, and Clonal Succession: The Evolution of the T Cell Response to Infection with a Persistent Virus J. Immunol., April 1, 2002; 168(7): 3309 - 3317. [Abstract] [Full Text] [PDF] |
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V. Appay, L. Papagno, C. A. Spina, P. Hansasuta, A. King, L. Jones, G. S. Ogg, S. Little, A. J. McMichael, D. D. Richman, et al. Dynamics of T Cell Responses in HIV Infection J. Immunol., April 1, 2002; 168(7): 3660 - 3666. [Abstract] [Full Text] [PDF] |
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J. Harbertson, E. Biederman, K. E. Bennett, R. M. Kondrack, and L. M. Bradley Withdrawal of Stimulation May Initiate the Transition of Effector to Memory CD4 Cells J. Immunol., February 1, 2002; 168(3): 1095 - 1102. [Abstract] [Full Text] [PDF] |
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T. Yajima, H. Nishimura, R. Ishimitsu, T. Watase, D. H. Busch, E. G. Pamer, H. Kuwano, and Y. Yoshikai Overexpression of IL-15 In Vivo Increases Antigen-Driven Memory CD8+ T Cells Following a Microbe Exposure J. Immunol., February 1, 2002; 168(3): 1198 - 1203. [Abstract] [Full Text] [PDF] |
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X. Zhang, H. Fujii, H. Kishimoto, E. LeRoy, C. D. Surh, and J. Sprent Aging Leads to Disturbed Homeostasis of Memory Phenotype CD8+ Cells J. Exp. Med., January 28, 2002; 195(3): 283 - 293. [Abstract] [Full Text] [PDF] |
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S. Zhou, R. Ou, L. Huang, and D. Moskophidis Critical Role for Perforin-, Fas/FasL-, and TNFR1-Mediated Cytotoxic Pathways in Down-Regulation of Antigen-Specific T Cells during Persistent Viral Infection J. Virol., January 15, 2002; 76(2): 829 - 840. [Abstract] [Full Text] [PDF] |
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T.-S. Wu, J.-M. Lee, Y.-G. Lai, J.-C. Hsu, C.-Y. Tsai, Y.-H. Lee, and N.-S. Liao Reduced Expression of Bcl-2 in CD8+ T Cells Deficient in the IL-15 Receptor {alpha}-Chain J. Immunol., January 15, 2002; 168(2): 705 - 712. [Abstract] [Full Text] [PDF] |
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S. Szmania, A. Galloway, M. Bruorton, P. Musk, G. Aubert, A. Arthur, H. Pyle, N. Hensel, N. Ta, L. Lamb Jr, et al. Isolation and expansion of cytomegalovirus-specific cytotoxic T lymphocytes to clinical scale from a single blood draw using dendritic cells and HLA-tetramers Blood, August 1, 2001; 98(3): 505 - 512. [Abstract] [Full Text] [PDF] |
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T. Ohteki, C. Maki, and S. Koyasu Overexpression of Bcl-2 Differentially Restores Development of Thymus-Derived CD4-8+ T Cells and Intestinal Intraepithelial T Cells in IFN-Regulatory Factor-1-Deficient Mice J. Immunol., June 1, 2001; 166(11): 6509 - 6513. [Abstract] [Full Text] [PDF] |
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E. Y. Choi, Y. Yoshimura, G. J. Christianson, T. J. Sproule, S. Malarkannan, N. Shastri, S. Joyce, and D. C. Roopenian Quantitative Analysis of the Immune Response to Mouse Non-MHC Transplantation Antigens In Vivo: The H60 Histocompatibility Antigen Dominates Over All Others J. Immunol., April 1, 2001; 166(7): 4370 - 4379. [Abstract] [Full Text] [PDF] |
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N. T. Young, M. Uhrberg, J. H. Phillips, L. L. Lanier, and P. Parham Differential Expression of Leukocyte Receptor Complex-Encoded Ig-Like Receptors Correlates with the Transition from Effector to Memory CTL J. Immunol., March 15, 2001; 166(6): 3933 - 3941. [Abstract] [Full Text] [PDF] |
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F. J. Plunkett, M. V. D. Soares, N. Annels, A. Hislop, K. Ivory, M. Lowdell, M. Salmon, A. Rickinson, and A. N. Akbar The flow cytometric analysis of telomere length in antigen-specific CD8+ T cells during acute Epstein-Barr virus infection Blood, February 1, 2001; 97(3): 700 - 707. [Abstract] [Full Text] [PDF] |
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J. M. Grayson, K. Murali-Krishna, J. D. Altman, and R. Ahmed Gene Expression in Antigen-Specific CD8+ T Cells During Viral Infection J. Immunol., January 15, 2001; 166(2): 795 - 799. [Abstract] [Full Text] [PDF] |
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R. Holtappels, M.-F. Pahl-Seibert, D. Thomas, and M. J. Reddehase Enrichment of Immediate-Early 1 (m123/pp89) Peptide-Specific CD8 T Cells in a Pulmonary CD62Llo Memory-Effector Cell Pool during Latent Murine Cytomegalovirus Infection of the Lungs J. Virol., December 15, 2000; 74(24): 11495 - 11503. [Abstract] [Full Text] |
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P. Shankar, M. Russo, B. Harnisch, M. Patterson, P. Skolnik, and J. Lieberman Impaired function of circulating HIV-specific CD8+ T cells in chronic human immunodeficiency virus infection Blood, November 1, 2000; 96(9): 3094 - 3101. [Abstract] [Full Text] [PDF] |
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A. D. Hislop, N. E. Annels, N. H. Gudgeon, A. M. Leese, and A. B. Rickinson Epitope-specific Evolution of Human CD8+ T Cell Responses from Primary to Persistent Phases of Epstein-Barr Virus Infection J. Exp. Med., April 1, 2002; 195(7): 893 - 905. [Abstract] [Full Text] [PDF] |
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