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Science 321 (5887): 408-411

Copyright © 2008 by the American Association for the Advancement of Science

Anomalous Type 17 Response to Viral Infection by CD8+ T Cells Lacking T-bet and Eomesodermin

Andrew M. Intlekofer,1,2 Arnob Banerjee,1,2 Naofumi Takemoto,1,2 Scott M. Gordon,1,2 Caitlin S. DeJong,1,2 Haina Shin,5 Christopher A. Hunter,4 E. John Wherry,5 Tullia Lindsten,1,3 Steven L. Reiner1,2*

Abstract: When intracellular pathogens invade mammalian hosts, naïve CD8+ T cells differentiate into cytotoxic killers, which lyse infected target cells and secrete cytokines that activate intracellular microbicides. We show that CD8+ T cells deficient in the transcription factors T-bet and eomesodermin (Eomes) fail to differentiate into functional killers required for defense against lymphocytic choriomeningitis virus. Instead, virus-specific CD8+ T cells lacking both T-bet and Eomes differentiate into an interleukin-17–secreting lineage, reminiscent of the helper T cell fate that has been implicated in autoimmunity and extracellular microbial defense. Upon viral infection, mice with T cells lacking both T-bet and Eomes develop a CD8+ T cell–dependent, progressive inflammatory and wasting syndrome characterized by multi-organ infiltration of neutrophils. T-bet and Eomes, thus, ensure that CD8+ T cells adopt an appropriate course of intracellular rather than extracellular destruction.

1 Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
2 Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
3 Department of Pathology, University of Pennsylvania, Philadelphia, PA 19104, USA.
4 Department of Pathobiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
5 Immunology Program, The Wistar Institute, Philadelphia, PA 19104, USA.

* To whom correspondence should be addressed at the Abramson Family Cancer Research Institute, University of Pennsylvania, Building BRB II/III, Room 414, 421 Curie Boulevard, Philadelphia, PA 19104–6160, USA. E-mail: sreiner{at}

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   Abstract »    Full Text »    PDF »
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Y. Zhu, S. Ju, E. Chen, S. Dai, C. Li, P. Morel, L. Liu, X. Zhang, and B. Lu (2010)
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   Abstract »    Full Text »    PDF »
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N. Yeh, N. L. Glosson, N. Wang, L. Guindon, C. McKinley, H. Hamada, Q. Li, R. W. Dutton, P. Shrikant, B. Zhou, et al. (2010)
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H. D. Marshall, A. L. Prince, L. J. Berg, and R. M. Welsh (2010)
J. Immunol. 185, 1419-1428
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C. Hervouet, C. Luci, N. Rol, D. Rousseau, A. Kissenpfennig, B. Malissen, C. Czerkinsky, and F. Anjuere (2010)
J. Immunol. 184, 4842-4851
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Analysis of CD161 expression on human CD8+ T cells defines a distinct functional subset with tissue-homing properties.
E. Billerbeck, Y.-H. Kang, L. Walker, H. Lockstone, S. Grafmueller, V. Fleming, J. Flint, C. B. Willberg, B. Bengsch, B. Seigel, et al. (2010)
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   Abstract »    Full Text »    PDF »
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L. Riol-Blanco, V. Lazarevic, A. Awasthi, M. Mitsdoerffer, B. S. Wilson, A. Croxford, A. Waisman, V. K. Kuchroo, L. H. Glimcher, and M. Oukka (2010)
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   Abstract »    Full Text »    PDF »
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S. T. Passos, J. S. Silver, A. C. O'Hara, D. Sehy, J. S. Stumhofer, and C. A. Hunter (2010)
J. Immunol. 184, 1776-1783
   Abstract »    Full Text »    PDF »
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H.-R. Yen, T. J. Harris, S. Wada, J. F. Grosso, D. Getnet, M. V. Goldberg, K.-L. Liang, T. C. Bruno, K. J. Pyle, S.-L. Chan, et al. (2009)
J. Immunol. 183, 7161-7168
   Abstract »    Full Text »    PDF »
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C. N. Jenne, A. Enders, R. Rivera, S. R. Watson, A. J. Bankovich, J. P. Pereira, Y. Xu, C. M. Roots, J. N. Beilke, A. Banerjee, et al. (2009)
J. Exp. Med. 206, 2469-2481
   Abstract »    Full Text »    PDF »
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L. Wang and R. Bosselut (2009)
J. Immunol. 183, 2903-2910
   Abstract »    Full Text »    PDF »
Type 17 CD8+ T cells display enhanced antitumor immunity.
C. S. Hinrichs, A. Kaiser, C. M. Paulos, L. Cassard, L. Sanchez-Perez, B. Heemskerk, C. Wrzesinski, Z. A. Borman, P. Muranski, and N. P. Restifo (2009)
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   Abstract »    Full Text »    PDF »
Histone Acetyltransferase CBP Is Vital To Demarcate Conventional and Innate CD8+ T-Cell Development.
T. Fukuyama, L. H. Kasper, F. Boussouar, T. Jeevan, J. van Deursen, and P. K. Brindle (2009)
Mol. Cell. Biol. 29, 3894-3904
   Abstract »    Full Text »    PDF »
IL-23 Promotes the Production of IL-17 by Antigen-Specific CD8 T Cells in the Absence of IL-12 and Type-I Interferons.
M. M. Curtis, S. S. Way, and C. B. Wilson (2009)
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   Abstract »    Full Text »    PDF »
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X. Yuan, M. J. Ansari, F. D'Addio, J. Paez-Cortez, I. Schmitt, M. Donnarumma, O. Boenisch, X. Zhao, J. Popoola, M. R. Clarkson, et al. (2009)
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   Abstract »    Full Text »    PDF »
T-bet Inhibits the In Vivo Differentiation of Parasite-Specific CD4+ Th17 Cells in a T Cell-Intrinsic Manner.
S. Guo, D. Cobb, and R. B. Smeltz (2009)
J. Immunol. 182, 6179-6186
   Abstract »    Full Text »    PDF »
TLR Signals Promote IL-6/IL-17-Dependent Transplant Rejection.
L. Chen, E. Ahmed, T. Wang, Y. Wang, J. Ochando, A. S. Chong, and M.-L. Alegre (2009)
J. Immunol. 182, 6217-6225
   Abstract »    Full Text »    PDF »
IL-23 Drives Pathogenic IL-17-Producing CD8+ T Cells.
B. Ciric, M. El-behi, R. Cabrera, G.-X. Zhang, and A. Rostami (2009)
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   Abstract »    Full Text »    PDF »
Th17 cells enhance viral persistence and inhibit T cell cytotoxicity in a model of chronic virus infection.
W. Hou, H. S. Kang, and B. S. Kim (2009)
J. Exp. Med. 206, 313-328
   Abstract »    Full Text »    PDF »
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F. Cruz-Guilloty, M. E. Pipkin, I. M. Djuretic, D. Levanon, J. Lotem, M. G. Lichtenheld, Y. Groner, and A. Rao (2009)
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   Abstract »    Full Text »    PDF »

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