Journal of Experimental Medicine, Vol 182, 1505-1515, Copyright © 1995 by Rockefeller University Press

ARTICLES

Interleukin (IL) 4, in the absence of antigen stimulation, induces an anergy-like state in differentiated CD8+ TC1 cells: loss of IL-2 synthesis and autonomous proliferation but retention of cytotoxicity and synthesis of other cytokines

S Sad and TR Mosmann
Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Canada.

Naive T cells in the periphery mainly secrete interleukin (IL) 2 upon activation. After stimulation in the presence of appropriate costimulators, both CD4+ and CD8+ T cells differentiate into effector cells secreting distinct T helper (Th) 1- and Th2-like cytokine patterns. Subsequent to differentiation, both CD4+ (Th1 and Th2) and CD8+ (TC1 and TC2) cells are stable and cannot be induced to differentiate into the opposite pattern or revert to the naive cytokine secretion pattern. We now show that IL-4 caused committed TC1 bulk populations or clones to lose the ability to synthesize IL-2. The cells retained the ability to secrete interferon (IFN) gamma, granulocyte/macrophage colony-stimulating factor, and tumor necrosis factor, did not synthesize any Th2 cytokines, and did not alter cell surface marker expression. IL-4 rapidly inhibited IL-2-synthesizing ability in the absence or presence of antigen-presenting cells, thus demonstrating that IL-4 acted directly on TC1 cells. The defect in IL-2 synthesis could not be reversed by subsequent stimulation with potent antigen-presenting cells in the presence of IL-2 and anti-IL-4, or with anti-CD3 plus anti-CD28 antibodies. Both IL-2+ and IL-2- TC1 cells were strongly cytotoxic toward allogeneic but not syngeneic targets. However, IL-2- TC1 cells were unable to proliferate unless exogenous IL- 2 was provided. TC1 cells that lose IL-2 synthesis but retain IFN-gamma synthesis and cytotoxicity may be similar to the "anergic" cells induced by stimulation of CD4+ or CD8+ cells in the absence of costimulators. These results suggest that during a mixed type 1/type 2 response in vivo, IL-4 may induce the IL-2+ TC1-->IL-2-TC1 conversion, and thus curtail the expansion of the TC1 response without impairing short-term effector function.
CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

• Makris, D., Lazarou, S., Alexandrakis, M., Kourelis, T. V., Tzanakis, N., Kyriakou, D., Gourgoulianis, K. I. (2008). Tc2 Response at the Onset of COPD Exacerbations. Chest 134: 483-488 [Abstract] [Full Text]  
• Chapdelaine, Y., Smith, D. K., Pedras-Vasconcelos, J. A., Krishnan, L., Sad, S. (2003). Increased CD8+ T Cell Memory to Concurrent Infection at the Expense of Increased Erosion of Pre-existing Memory: The Paradoxical Role of IL-15. J. Immunol. 171: 5454-5460 [Abstract] [Full Text]  
• Dudani, R., Chapdelaine, Y., van Faassen, H., Smith, D. K., Shen, H., Krishnan, L., Sad, S. (2002). Preexisting Inflammation Due to Mycobacterium bovis BCG Infection Differentially Modulates T-Cell Priming against a Replicating or Nonreplicating Immunogen. Infect. Immun. 70: 1957-1964 [Abstract] [Full Text]  
• Argibay, P. F., Di Noia, J. M., Hidalgo, A., Mocetti, E., Barbich, M., Lorenti, A. S., Bustos, D., Tambutti, M., Hyon, S. H., Frasch, A. C.C., Sanchez, D. O. (2002). Trypanosoma cruzi surface mucin TcMuc-e2 expressed on higher eukaryotic cells induces human T cell anergy, which is reversible. Glycobiology 12: 25-32 [Abstract] [Full Text]  
• Chung, K.F. (2001). Cytokines in chronic obstructive pulmonary disease. Eur Respir J 18: 50S-59s [Abstract] [Full Text]  
• Vukmanovic-Stejic, M., Vyas, B., Gorak-Stolinska, P., Noble, A., Kemeny, D. M. (2000). Human Tc1 and Tc2/Tc0 CD8 T-cell clones display distinct cell surface and functional phenotypes. Blood 95: 231-240 [Abstract] [Full Text]  
• KEMENY, D. M., VYAS, B., VUKMANOVIC-STEJIC, M., THOMAS, M. J., NOBLE, A., LOH, L.-C., O'CONNOR, B. J. (1999). CD8+ T Cell Subsets and Chronic Obstructive Pulmonary Disease. Am. J. Respir. Crit. Care Med. 160: S33-37 [Abstract] [Full Text]  
• Sad, S., Krishnan, L. (1999). Cytokine Deprivation of Naive CD8+ T Cells Promotes Minimal Cell Cycling but Maximal Cytokine Synthesis and Autonomous Proliferation Subsequently: A Mechanism of Self-Regulation. J. Immunol. 163: 2443-2451 [Abstract] [Full Text]  
• Gullo, C. A., Esser, M. T., Fuller, C. L., Braciale, V. L. (1999). Generation of IL-2-Dependent Cytolytic T Lymphocytes (CTLs) with Altered TCR Responses Derived from Antigen-Dependent CTL Clones. J. Immunol. 162: 6466-6472 [Abstract] [Full Text]  
• Villacres, M. C., Bergmann, C. C. (1999). Enhanced Cytotoxic T Cell Activity in IL-4-Deficient Mice. J. Immunol. 162: 2663-2670 [Abstract] [Full Text]  
• Rivoltini, L., Squarcina, P., Loftus, D. J., Castelli, C., Tarsini, P., Mazzocchi, A., Rini, F., Viggiano, V., Belli, F., Parmiani, G. (1999). A Superagonist Variant of Peptide MART1/Melan A27-35 Elicits Anti-Melanoma CD8+ T Cells with Enhanced Functional Characteristics: Implication for More Effective Immunotherapy. Cancer Res. 59: 301-306 [Abstract] [Full Text]  
• Kemeny, M., Peakman, M. (1998). Recent advances: Immunology. BMJ 316: 600-603 [Full Text]  
• Kelso, A., Groves, P. (1997). A single peripheral CD8+ T cell can give rise to progeny expressing type 1 and/or type 2 cytokine genes and can retain its multipotentiality through many cell divisions. Proc. Natl. Acad. Sci. USA 94: 8070-8075 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS