International Immunology, Vol. 11, No. 2, 229-241,
February 1999
© 1999 Japanese Society for Immunology
Differentiation of human CD8 T cells: implications for in vivo persistence of CD8+CD28– cytotoxic effector clones
Immunology Program, Graduate School of Medical Sciences, and the Department of Medicine, Cornell University, Weill Medical College, 1300 York Avenue, Box 56, New York, NY 10021
Correspondence to: D. N. Posnett
CD8 T cells contain a distinct subset of CD8+CD28– cells. These cells are not present at birth and their frequency increases with age. They frequently contain expanded clones using various TCR
ß receptors and these clones can represent >50% of all CD8 cells, specially in old subjects or patients with chronic viral infections such as HIV-1. Herein, it is shown that a large fraction of CD8+CD28– cells expresses intracellular perforin by three-color flow cytometry, in particular when this subset is expanded. Together with their known ability to exert potent re-directed cytotoxicity, this indicates that CD8+CD28– T cells comprise cytotoxic effector cells. With BrdU labeling, we show that CD8+CD28– cells derive from CD8+CD28+ precursors in vitro. In addition, sorted CD8+CD28+ cells gave rise to a population of CD8+CD28– cells after allo-stimulation. Moreover, ex vivo CD8+CD28+ cells contain the majority of CD8 blasts, supporting the notion that they contain the proliferative precursors of CD8+CD28– cells. CD95 (Fas) expression was lower in CD8+CD28– cells, and this subset was less prone to spontaneous apoptosis in ex vivo samples and more resistant to activation-induced cell death induced by a superantigen in vitro. Thus, the persistence of expanded clones in vivo in the CD8+CD28– subset may be explained by antigen-driven differentiation from CD8+CD28+ memory precursors, with relative resistance to apoptosis as the clones become perforin+ effector cells.
Keywords: age, apoptosis, CD8, CD28, human, oligoclonal, TCR
Transmitting editor: A. Singer
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  M. Inokuma, C. dela Rosa, C. Schmitt, P. Haaland, J. Siebert, D. Petry, M. Tang, M. A. Suni, S. A. Ghanekar, D. Gladding, et al. Functional T Cell Responses to Tumor Antigens in Breast Cancer Patients Have a Distinct Phenotype and Cytokine Signature J. Immunol., August 15, 2007; 179(4): 2627 - 2633. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. D. Wu, M. S. Maurer, R. A. Friedman, C. C. Marboe, E. M. Ruiz-Vazquez, R. Ramakrishnan, A. Schwartz, M. D. Tilson, A. S. Stewart, and R. Winchester The Lymphocytic Infiltration in Calcific Aortic Stenosis Predominantly Consists of Clonally Expanded T Cells J. Immunol., April 15, 2007; 178(8): 5329 - 5339. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. C. Beier, T. Kallinich, and E. Hamelmann Master switches of T-cell activation and differentiation Eur. Respir. J., April 1, 2007; 29(4): 804 - 812. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Barbey, P. Baumgaertner, E. Devevre, V. Rubio-Godoy, L. Derre, G. Bricard, P. Guillaume, I. F. Luescher, D. Lienard, J.-C. Cerottini, et al. IL-12 Controls Cytotoxicity of a Novel Subset of Self-Antigen-Specific Human CD28+ Cytolytic T Cells J. Immunol., March 15, 2007; 178(6): 3566 - 3574. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. K. Chiu, M. Fann, and N.-p. Weng Generation and Growth of CD28nullCD8+ Memory T Cells Mediated by IL-15 and Its Induced Cytokines J. Immunol., December 1, 2006; 177(11): 7802 - 7810. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Kobayashi, T. Kondo, H. Takata, S. Yokota, and M. Takiguchi Functional and phenotypic analysis of human memory CD8+ T cells expressing CXCR3. J. Leukoc. Biol., August 1, 2006; 80(2): 320 - 329. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Heydtmann, D. Hardie, P. L. Shields, J. Faint, C. D. Buckley, J. J. Campbell, M. Salmon, and D. H. Adams Detailed Analysis of Intrahepatic CD8 T Cells in the Normal and Hepatitis C-Infected Liver Reveals Differences in Specific Populations of Memory Cells with Distinct Homing Phenotypes J. Immunol., July 1, 2006; 177(1): 729 - 738. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Fletcher, M. Vukmanovic-Stejic, P. J. Dunne, K. E. Birch, J. E. Cook, S. E. Jackson, M. Salmon, M. H. Rustin, and A. N. Akbar Cytomegalovirus-Specific CD4+ T Cells in Healthy Carriers Are Continuously Driven to Replicative Exhaustion J. Immunol., December 15, 2005; 175(12): 8218 - 8225. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Wikby, F. Ferguson, R. Forsey, J. Thompson, J. Strindhall, S. Lofgren, B.-O. Nilsson, J. Ernerudh, G. Pawelec, and B. Johansson An Immune Risk Phenotype, Cognitive Impairment, and Survival in Very Late Life: Impact of Allostatic Load in Swedish Octogenarian and Nonagenarian Humans J. Gerontol. A Biol. Sci. Med. Sci., May 1, 2005; 60(5): 556 - 565. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Messaoudi, J. LeMaoult, J. A. Guevara-Patino, B. M. Metzner, and J. Nikolich-Zugich Age-related CD8 T Cell Clonal Expansions Constrict CD8 T Cell Repertoire and Have the Potential to Impair Immune Defense J. Exp. Med., November 15, 2004; 200(10): 1347 - 1358. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. H. Undale, P. J. van den Elsen, and E. Celis Antigen-independent acquisition of MHC class II molecules by human T lymphocytes Int. Immunol., October 1, 2004; 16(10): 1523 - 1533. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. L. Wallace, Y. Zhang, H. Ghattas, A. Worth, A. Irvine, A. R. Bennett, G. E. Griffin, P. C. L. Beverley, D. F. Tough, and D. C. Macallan Direct Measurement of T Cell Subset Kinetics In Vivo in Elderly Men and Women J. Immunol., August 1, 2004; 173(3): 1787 - 1794. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. E. Lewis, M. Merched-Sauvage, J. J. Goronzy, C. M. Weyand, and A. N. Vallejo Tumor Necrosis Factor-{alpha} and CD80 Modulate CD28 Expression through a Similar Mechanism of T-cell Receptor-independent Inhibition of Transcription J. Biol. Chem., July 9, 2004; 279(28): 29130 - 29138. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. D. Peacock and R. M. Welsh Origin and Fate of Lymphocytic Choriomeningitis Virus-Specific CD8+ T Cells Coexpressing the Inhibitory NK Cell Receptor Ly49G2 J. Immunol., July 1, 2004; 173(1): 478 - 484. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Jankovic, I. Messaoudi, and J. Nikolich-Zugich Phenotypic and functional T-cell aging in rhesus macaques (Macaca mulatta): differential behavior of CD4 and CD8 subsets Blood, November 1, 2003; 102(9): 3244 - 3251. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. S. Topp, S. R. Riddell, Y. Akatsuka, M. C. Jensen, J. N. Blattman, and P. D. Greenberg Restoration of CD28 Expression in CD28- CD8+ Memory Effector T Cells Reconstitutes Antigen-induced IL-2 Production J. Exp. Med., September 15, 2003; 198(6): 947 - 955. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Amyes, C. Hatton, D. Montamat-Sicotte, N. Gudgeon, A. B. Rickinson, A. J. McMichael, and M. F.C. Callan Characterization of the CD4+ T Cell Response to Epstein-Barr Virus during Primary and Persistent Infection J. Exp. Med., September 15, 2003; 198(6): 903 - 911. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Geginat, A. Lanzavecchia, and F. Sallusto Proliferation and differentiation potential of human CD8+ memory T-cell subsets in response to antigen or homeostatic cytokines Blood, June 1, 2003; 101(11): 4260 - 4266. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. J. Warrington, A. N. Vallejo, C. M. Weyand, and J. J. Goronzy CD28 loss in senescent CD4+ T cells: reversal by interleukin-12 stimulation Blood, May 1, 2003; 101(9): 3543 - 3549. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Bigouret, T. Hoffmann, L. Arlettaz, J. Villard, M. Colonna, A. Ticheli, A. Gratwohl, K. Samii, B. Chapuis, N. Rufer, et al. Monoclonal T-cell expansions in asymptomatic individuals and in patients with large granular leukemia consist of cytotoxic effector T cells expressing the activating CD94:NKG2C/E and NKD2D killer cell receptors Blood, April 15, 2003; 101(8): 3198 - 3204. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Voehringer, M. Koschella, and H. Pircher Lack of proliferative capacity of human effector and memory T cells expressing killer cell lectinlike receptor G1 (KLRG1) Blood, November 15, 2002; 100(10): 3698 - 3702. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-J. Kim, R. R. Brutkiewicz, and H. E. Broxmeyer Role of 4-1BB (CD137) in the functional activation of cord blood CD28-CD8+ T cells Blood, October 16, 2002; 100(9): 3253 - 3260. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Walzer, C. Arpin, L. Beloeil, and J. Marvel Differential In Vivo Persistence of Two Subsets of Memory Phenotype CD8 T Cells Defined by CD44 and CD122 Expression Levels J. Immunol., March 15, 2002; 168(6): 2704 - 2711. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Holznagel, S. Norley, S. Holzammer, C. Coulibaly, and R. Kurth Immunological changes in simian immunodeficiency virus (SIVagm)-infected African green monkeys (AGM): expanded cytotoxic T lymphocyte, natural killer and B cell subsets in the natural host of SIVagm J. Gen. Virol., March 1, 2002; 83(3): 631 - 640. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. J. Pitcher, S. I. Hagen, J. M. Walker, R. Lum, B. L. Mitchell, V. C. Maino, M. K. Axthelm, and L. J. Picker Development and Homeostasis of T Cell Memory in Rhesus Macaque J. Immunol., January 1, 2002; 168(1): 29 - 43. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Suresh, J. K. Whitmire, L. E. Harrington, C. P. Larsen, T. C. Pearson, J. D. Altman, and R. Ahmed Role of CD28-B7 Interactions in Generation and Maintenance of CD8 T Cell Memory J. Immunol., November 15, 2001; 167(10): 5565 - 5573. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Nishio, M. Suzuki, N. Miyasaka, and H. Kohsaka Clonal Biases of Peripheral CD8 T Cell Repertoire Directly Reflect Local Inflammation in Polymyositis J. Immunol., October 1, 2001; 167(7): 4051 - 4058. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. D. Hislop, N. H. Gudgeon, M. F. C. Callan, C. Fazou, H. Hasegawa, M. Salmon, and A. B. Rickinson EBV-Specific CD8+ T Cell Memory: Relationships Between Epitope Specificity, Cell Phenotype, and Immediate Effector Function J. Immunol., August 15, 2001; 167(4): 2019 - 2029. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. A. Trimble, L. W. Kam, R. S. Friedman, Z. Xu, and J. Lieberman CD3zeta and CD28 down-modulation on CD8 T cells during viral infection Blood, August 1, 2000; 96(3): 1021 - 1029. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Appay, D. F. Nixon, S. M. Donahoe, G. M.A. Gillespie, T. Dong, A. King, G. S. Ogg, H. M.L. Spiegel, C. Conlon, C. A. Spina, et al. HIV-specific CD8+ T Cells Produce Antiviral Cytokines but Are Impaired in Cytolytic Function J. Exp. Med., July 3, 2000; 192(1): 63 - 76. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Pittet, D. E. Speiser, D. Valmori, J.-C. Cerottini, and P. Romero Cutting Edge: Cytolytic Effector Function in Human Circulating CD8+ T Cells Closely Correlates with CD56 Surface Expression J. Immunol., February 1, 2000; 164(3): 1148 - 1152. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Pittet, D. Valmori, P. R. Dunbar, D. E. Speiser, D. Lienard, F. Lejeune, K. Fleischhauer, V. Cerundolo, J.-C. Cerottini, and P. Romero High Frequencies of Naive Melan-A/MART-1–specific CD8+ T Cells in a Large Proportion of Human Histocompatibility Leukocyte Antigen (HLA)-A2 Individuals J. Exp. Med., September 6, 1999; 190(5): 705 - 716. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Labalette, E. Leteurtre, C. Thumerelle, C. Grutzmacher, B. Tourvieille, and J.-P. Dessaint Peripheral human CD8+CD28+T lymphocytes give rise to CD28–progeny, but IL-4 prevents loss of CD28 expression Int. Immunol., August 1, 1999; 11(8): 1327 - 1336. [Abstract] [Full Text] [PDF]
|
|