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

doi:10.1126/science.1159806

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

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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, naïveCD8⁺ T cells differentiate into cytotoxic killers, which lyseinfected target cells and secrete cytokines that activate intracellularmicrobicides. We show that CD8⁺ T cells deficient in the transcriptionfactors T-bet and eomesodermin (Eomes) fail to differentiateinto functional killers required for defense against lymphocyticchoriomeningitis virus. Instead, virus-specific CD8⁺ T cellslacking both T-bet and Eomes differentiate into an interleukin-17–secretinglineage, reminiscent of the helper T cell fate that has beenimplicated in autoimmunity and extracellular microbial defense.Upon viral infection, mice with T cells lacking both T-bet andEomes develop a CD8⁺ T cell–dependent, progressive inflammatoryand wasting syndrome characterized by multi-organ infiltrationof neutrophils. T-bet and Eomes, thus, ensure that CD8⁺ T cellsadopt an appropriate course of intracellular rather than extracellulardestruction.

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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