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Science 18 July 2008:
Vol. 321. no. 5887, pp. 408 - 411
DOI: 10.1126/science.1159806
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Reports

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*

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}mail.med.upenn.edu

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